Nephrology

A third dose of a COVID-19 vaccine can boost antibody levels in people who previously received a solid organ transplant and had an unsatisfactory response to their first two mRNA shots, according to data from a newly published 30-patient case series.

All of those with low titers before the third dose had high titers after receiving the additional shot, but only about 33% of those with negative initial responses had detectable antibodies after the third dose, according to the paper, published in Annals of Internal Medicine.

Researchers at Johns Hopkins, Baltimore, who keep a COVID-19 vaccine registry, perform antibody tests on all registry subjects and inform them of their results. Registry participants were asked to inform the research team if they received a third dose, and, the research team tracked the immune responses of those who did.

The participants in this case series had low antibody levels and received a third dose of the vaccine on their own between March 20 and May 10 of 2021.
 

Third dose results

In this cases series – thought to be the first to look at third vaccine shots in this type of patient group – all six of those who had low antibody titers before the third dose had high-positive titers after the third dose.

Of the 24 individuals who had negative antibody titers before the third dose, just 6 had high titers after the third dose.

Two of the participants had low-positive titers, and 16 were negative.

“Several of those boosted very nicely into ranges seen, using these assays, in healthy persons,” said William Werbel, MD, a fellow in infectious disease at Johns Hopkins Medicine, Baltimore, who helped lead the study. Those with negative levels, even if they responded, tended to have lower titers, he said.

“The benefits at least from an antibody perspective were not the same for everybody and so this is obviously something that needs to be considered when thinking about selecting patients” for a COVID-19 prevention strategy, he said.

Reactions to the vaccine were low to moderate, such as some arm pain and fatigue.

“Showing that something is safe in that special, vulnerable population is important,” Dr. Werbel said. “We’re all wanting to make sure that we’re doing no harm.”

Dr. Werbel noted that there was no pattern in the small series based on the organ transplanted or in the vaccines used. As their third shot, 15 of the patients received the Johnson & Johnson vaccine; 9 received Moderna; and 6 received Pfizer-BioNTech.
 

Welcome news, but larger studies needed

“To think that a third dose could confer protection for a significant number of people is of course extremely welcome news,” said Christian Larsen, MD, DPhil, professor of surgery in the transplantation division at Emory University, Atlanta, who was not involved in the study. “It’s the easiest conceivable next intervention.”

He added, “We just want studies to confirm that – larger studies.”

Dr. Werbel stressed the importance of looking at third doses in these patients in a more controlled fashion in a randomized trial, to more carefully monitor safety and how patients fare when starting with one type of vaccine and switching to another, for example.

Richard Wender, MD, chair of family medicine and community health at the University of Pennsylvania, Philadelphia, said the findings are a reminder that there is still a lot that is unknown about COVID-19 and vaccination.

“We still don’t know who will or will not benefit from a third dose,” he said. “And our knowledge is evolving.  For example, a recent study suggested that people with previous infection and who are vaccinated may have better and longer protection than people with vaccination alone. We’re still learning.”

He added that specialists, not primary care clinicians, should be relied upon to respond to this emerging vaccination data. Primary care doctors are very busy in other ways – such as in getting children caught up on vaccinations and helping adults return to managing their chronic diseases, Dr. Wender noted.

“Their focus needs to be on helping to overcome hesitancy, mistrust, lack of information, or antivaccination sentiment to help more people feel comfortable being vaccinated – this is a lot of work and needs constant focus. In short, primary care clinicians need to focus chiefly on the unvaccinated,” he said.

“Monitoring immunization recommendations for unique at-risk populations should be the chief responsibility of teams providing subspecialty care, [such as for] transplant patients, people with chronic kidney disease, cancer patients, and people with other chronic illnesses.  This will allow primary care clinicians to tackle their many complex jobs.”
 

Possible solutions for those with low antibody responses

Dr. Larsen said that those with ongoing low antibody responses might still have other immune responses, such as a T-cell response. Such patients also could consider changing their vaccine type, he said.

“At the more significant intervention level, there may be circumstances where one could change the immunosuppressive drugs in a controlled way that might allow a better response,” suggested Dr. Larsen. “That’s obviously going to be something that requires a lot more thought and careful study.”

Dr. Werbel said that other options might need to be considered for those having no response following a third dose. One possibility is trying a vaccine with an adjuvant, such as the Novavax version, which might be more widely available soon.

“If you’re given a third dose of a very immunogenic vaccine – something that should work – and you just have no antibody development, it seems relatively unlikely that doing the same thing again is going to help you from that perspective, and for all we know might expose you to more risk,” Dr. Werbel noted.
 

Participant details

None of the 30 patients were thought to have ever had COVID-19. On average, patients had received their transplant 4.5 years before their original vaccination. In 25 patients, maintenance immunosuppression included tacrolimus or cyclosporine along with mycophenolate. Corticosteroids were also used for 24 patients, sirolimus was used for one patient, and belatacept was used for another patient.

Fifty-seven percent of patients had received the Pfizer/BioNTech vaccine originally, and 43% the Moderna vaccine. Most of the patients were kidney recipients, with two heart, three liver, one lung, one pancreas and one kidney-pancreas.

Dr. Werbel, Dr. Wender, and Dr. Larsen reported no relevant disclosures.

A third dose of a COVID-19 vaccine can boost antibody levels in people who previously received a solid organ transplant and had an unsatisfactory response to their first two mRNA shots, according to data from a newly published 30-patient case series.

All of those with low titers before the third dose had high titers after receiving the additional shot, but only about 33% of those with negative initial responses had detectable antibodies after the third dose, according to the paper, published in Annals of Internal Medicine.

Researchers at Johns Hopkins, Baltimore, who keep a COVID-19 vaccine registry, perform antibody tests on all registry subjects and inform them of their results. Registry participants were asked to inform the research team if they received a third dose, and, the research team tracked the immune responses of those who did.

The participants in this case series had low antibody levels and received a third dose of the vaccine on their own between March 20 and May 10 of 2021.
 

Third dose results

In this cases series – thought to be the first to look at third vaccine shots in this type of patient group – all six of those who had low antibody titers before the third dose had high-positive titers after the third dose.

Of the 24 individuals who had negative antibody titers before the third dose, just 6 had high titers after the third dose.

Two of the participants had low-positive titers, and 16 were negative.

“Several of those boosted very nicely into ranges seen, using these assays, in healthy persons,” said William Werbel, MD, a fellow in infectious disease at Johns Hopkins Medicine, Baltimore, who helped lead the study. Those with negative levels, even if they responded, tended to have lower titers, he said.

“The benefits at least from an antibody perspective were not the same for everybody and so this is obviously something that needs to be considered when thinking about selecting patients” for a COVID-19 prevention strategy, he said.

Reactions to the vaccine were low to moderate, such as some arm pain and fatigue.

“Showing that something is safe in that special, vulnerable population is important,” Dr. Werbel said. “We’re all wanting to make sure that we’re doing no harm.”

Dr. Werbel noted that there was no pattern in the small series based on the organ transplanted or in the vaccines used. As their third shot, 15 of the patients received the Johnson & Johnson vaccine; 9 received Moderna; and 6 received Pfizer-BioNTech.
 

Welcome news, but larger studies needed

“To think that a third dose could confer protection for a significant number of people is of course extremely welcome news,” said Christian Larsen, MD, DPhil, professor of surgery in the transplantation division at Emory University, Atlanta, who was not involved in the study. “It’s the easiest conceivable next intervention.”

He added, “We just want studies to confirm that – larger studies.”

Dr. Werbel stressed the importance of looking at third doses in these patients in a more controlled fashion in a randomized trial, to more carefully monitor safety and how patients fare when starting with one type of vaccine and switching to another, for example.

Richard Wender, MD, chair of family medicine and community health at the University of Pennsylvania, Philadelphia, said the findings are a reminder that there is still a lot that is unknown about COVID-19 and vaccination.

“We still don’t know who will or will not benefit from a third dose,” he said. “And our knowledge is evolving.  For example, a recent study suggested that people with previous infection and who are vaccinated may have better and longer protection than people with vaccination alone. We’re still learning.”

He added that specialists, not primary care clinicians, should be relied upon to respond to this emerging vaccination data. Primary care doctors are very busy in other ways – such as in getting children caught up on vaccinations and helping adults return to managing their chronic diseases, Dr. Wender noted.

“Their focus needs to be on helping to overcome hesitancy, mistrust, lack of information, or antivaccination sentiment to help more people feel comfortable being vaccinated – this is a lot of work and needs constant focus. In short, primary care clinicians need to focus chiefly on the unvaccinated,” he said.

“Monitoring immunization recommendations for unique at-risk populations should be the chief responsibility of teams providing subspecialty care, [such as for] transplant patients, people with chronic kidney disease, cancer patients, and people with other chronic illnesses.  This will allow primary care clinicians to tackle their many complex jobs.”
 

Possible solutions for those with low antibody responses

Dr. Larsen said that those with ongoing low antibody responses might still have other immune responses, such as a T-cell response. Such patients also could consider changing their vaccine type, he said.

“At the more significant intervention level, there may be circumstances where one could change the immunosuppressive drugs in a controlled way that might allow a better response,” suggested Dr. Larsen. “That’s obviously going to be something that requires a lot more thought and careful study.”

Dr. Werbel said that other options might need to be considered for those having no response following a third dose. One possibility is trying a vaccine with an adjuvant, such as the Novavax version, which might be more widely available soon.

“If you’re given a third dose of a very immunogenic vaccine – something that should work – and you just have no antibody development, it seems relatively unlikely that doing the same thing again is going to help you from that perspective, and for all we know might expose you to more risk,” Dr. Werbel noted.
 

Participant details

None of the 30 patients were thought to have ever had COVID-19. On average, patients had received their transplant 4.5 years before their original vaccination. In 25 patients, maintenance immunosuppression included tacrolimus or cyclosporine along with mycophenolate. Corticosteroids were also used for 24 patients, sirolimus was used for one patient, and belatacept was used for another patient.

Fifty-seven percent of patients had received the Pfizer/BioNTech vaccine originally, and 43% the Moderna vaccine. Most of the patients were kidney recipients, with two heart, three liver, one lung, one pancreas and one kidney-pancreas.

Dr. Werbel, Dr. Wender, and Dr. Larsen reported no relevant disclosures.

A third dose of a COVID-19 vaccine can boost antibody levels in people who previously received a solid organ transplant and had an unsatisfactory response to their first two mRNA shots, according to data from a newly published 30-patient case series.

All of those with low titers before the third dose had high titers after receiving the additional shot, but only about 33% of those with negative initial responses had detectable antibodies after the third dose, according to the paper, published in Annals of Internal Medicine.

Researchers at Johns Hopkins, Baltimore, who keep a COVID-19 vaccine registry, perform antibody tests on all registry subjects and inform them of their results. Registry participants were asked to inform the research team if they received a third dose, and, the research team tracked the immune responses of those who did.

The participants in this case series had low antibody levels and received a third dose of the vaccine on their own between March 20 and May 10 of 2021.
 

Third dose results

In this cases series – thought to be the first to look at third vaccine shots in this type of patient group – all six of those who had low antibody titers before the third dose had high-positive titers after the third dose.

Of the 24 individuals who had negative antibody titers before the third dose, just 6 had high titers after the third dose.

Two of the participants had low-positive titers, and 16 were negative.

“Several of those boosted very nicely into ranges seen, using these assays, in healthy persons,” said William Werbel, MD, a fellow in infectious disease at Johns Hopkins Medicine, Baltimore, who helped lead the study. Those with negative levels, even if they responded, tended to have lower titers, he said.

“The benefits at least from an antibody perspective were not the same for everybody and so this is obviously something that needs to be considered when thinking about selecting patients” for a COVID-19 prevention strategy, he said.

Reactions to the vaccine were low to moderate, such as some arm pain and fatigue.

“Showing that something is safe in that special, vulnerable population is important,” Dr. Werbel said. “We’re all wanting to make sure that we’re doing no harm.”

Dr. Werbel noted that there was no pattern in the small series based on the organ transplanted or in the vaccines used. As their third shot, 15 of the patients received the Johnson & Johnson vaccine; 9 received Moderna; and 6 received Pfizer-BioNTech.
 

Welcome news, but larger studies needed

“To think that a third dose could confer protection for a significant number of people is of course extremely welcome news,” said Christian Larsen, MD, DPhil, professor of surgery in the transplantation division at Emory University, Atlanta, who was not involved in the study. “It’s the easiest conceivable next intervention.”

He added, “We just want studies to confirm that – larger studies.”

Dr. Werbel stressed the importance of looking at third doses in these patients in a more controlled fashion in a randomized trial, to more carefully monitor safety and how patients fare when starting with one type of vaccine and switching to another, for example.

Richard Wender, MD, chair of family medicine and community health at the University of Pennsylvania, Philadelphia, said the findings are a reminder that there is still a lot that is unknown about COVID-19 and vaccination.

“We still don’t know who will or will not benefit from a third dose,” he said. “And our knowledge is evolving.  For example, a recent study suggested that people with previous infection and who are vaccinated may have better and longer protection than people with vaccination alone. We’re still learning.”

He added that specialists, not primary care clinicians, should be relied upon to respond to this emerging vaccination data. Primary care doctors are very busy in other ways – such as in getting children caught up on vaccinations and helping adults return to managing their chronic diseases, Dr. Wender noted.

“Their focus needs to be on helping to overcome hesitancy, mistrust, lack of information, or antivaccination sentiment to help more people feel comfortable being vaccinated – this is a lot of work and needs constant focus. In short, primary care clinicians need to focus chiefly on the unvaccinated,” he said.

“Monitoring immunization recommendations for unique at-risk populations should be the chief responsibility of teams providing subspecialty care, [such as for] transplant patients, people with chronic kidney disease, cancer patients, and people with other chronic illnesses.  This will allow primary care clinicians to tackle their many complex jobs.”
 

Possible solutions for those with low antibody responses

Dr. Larsen said that those with ongoing low antibody responses might still have other immune responses, such as a T-cell response. Such patients also could consider changing their vaccine type, he said.

“At the more significant intervention level, there may be circumstances where one could change the immunosuppressive drugs in a controlled way that might allow a better response,” suggested Dr. Larsen. “That’s obviously going to be something that requires a lot more thought and careful study.”

Dr. Werbel said that other options might need to be considered for those having no response following a third dose. One possibility is trying a vaccine with an adjuvant, such as the Novavax version, which might be more widely available soon.

“If you’re given a third dose of a very immunogenic vaccine – something that should work – and you just have no antibody development, it seems relatively unlikely that doing the same thing again is going to help you from that perspective, and for all we know might expose you to more risk,” Dr. Werbel noted.
 

Participant details

None of the 30 patients were thought to have ever had COVID-19. On average, patients had received their transplant 4.5 years before their original vaccination. In 25 patients, maintenance immunosuppression included tacrolimus or cyclosporine along with mycophenolate. Corticosteroids were also used for 24 patients, sirolimus was used for one patient, and belatacept was used for another patient.

Fifty-seven percent of patients had received the Pfizer/BioNTech vaccine originally, and 43% the Moderna vaccine. Most of the patients were kidney recipients, with two heart, three liver, one lung, one pancreas and one kidney-pancreas.

Dr. Werbel, Dr. Wender, and Dr. Larsen reported no relevant disclosures.

Background: With more than 500 cases of NSF reported during 1997-2007, a black box warning advises against use of all GBCAs in at-risk CKD patients. However, newer literature has shown that group II GBCAs may have lower risks of causing NSF. The risk to patients with CKD IV and V is not clear.

Dr. Midha is a hospitalist at Beth Israel Deaconess Medical Center, instructor of medicine, Boston University, and part-time instructor in medicine, Harvard Medical School, all in Boston.

Background: With more than 500 cases of NSF reported during 1997-2007, a black box warning advises against use of all GBCAs in at-risk CKD patients. However, newer literature has shown that group II GBCAs may have lower risks of causing NSF. The risk to patients with CKD IV and V is not clear.

Dr. Midha is a hospitalist at Beth Israel Deaconess Medical Center, instructor of medicine, Boston University, and part-time instructor in medicine, Harvard Medical School, all in Boston.

Background: With more than 500 cases of NSF reported during 1997-2007, a black box warning advises against use of all GBCAs in at-risk CKD patients. However, newer literature has shown that group II GBCAs may have lower risks of causing NSF. The risk to patients with CKD IV and V is not clear.

Dr. Midha is a hospitalist at Beth Israel Deaconess Medical Center, instructor of medicine, Boston University, and part-time instructor in medicine, Harvard Medical School, all in Boston.

Look ma, I’m writing with no hands

Imagine being able to type every thought you had without using your hands, the words just magically appearing on the screen as fast as you can think of writing them down. Well, with the help of a new brain-computer interface (BCI), you can.

In a recent paper published in Nature, a team of researchers described how they developed a whole new way of communicating that blows previous BCIs, which used a method of pointing and clicking on letters, out of the water as far as accuracy and speed are concerned.

Developed for individuals with medical conditions or other disabilities that prevent them from communicating verbally or manually, the technology involves placing tiny sensors on the brain in the areas that control hand and arm movements. All the individual has to do is think of the process of writing and the system does the rest.

©Thinkstock

Chicken noodle salmonella

Chickens and ducks sure are cute, especially babies, but humans should be extra careful around these animals for risk of salmonella. This isn’t a new thing to loyal readers of Livin’ on the MDedge.

As more people keep such creatures at home – Emily Shoop of Penn State University told the N.Y. Times that raising poultry was “the fastest-growing animal-related hobby in the United States” – the ducks and chickens are being treated more like house pets, which is sweet but not safe.

In the latest outbreak, more than 160 people, mostly children under 5 years old, have fallen ill from salmonella poisoning and more than 30 have been hospitalized across 43 states, and the Centers for Disease Control and Prevention suspects the numbers could be higher because many did not get tested and recovered on their own.

JasonJiron/Thinkstock

This kidney research rocks!

When kids pick teams on the playground, someone is going to get their feelings hurt by being chosen last. There’s no way around it. Someone has to be last.

It’s the same way with research teams. When scientists are trying to cure diseases or pioneer new surgical techniques, they get a team together. And who always gets picked last? That’s right, the geologist, because who needs a geologist when you’re studying brain-computer interfaces?

Turns out, though, that there was a research team that needed a geologist: The one studying kidney stones.

Illinois geology professor Bruce Fouke explains: “The process of kidney stone formation is part of the natural process of the stone formation seen throughout nature. We are bringing together geology, biology, and medicine to map the entire process of kidney stone formation, step by step.”

Mayandi Sivaguru

Gene therapy: What is it good for? Absolutely nothing!

Gene therapy has the potential to permanently cure all sorts of terrible diseases, and one would assume that this would be something we all could agree on. Yes, no more cancer or diabetes or anything like that, no sane person could possibly be against this, right?

Oh, you poor naive fool.

To be fair, the report written by Goldman Sachs does lay out many potential applications for gene therapy, and all the markets it can expand into. But then the writers ask the question that they’re not supposed to say out loud: Is curing patients a sustainable business model?

Pogonic/Getty Images

Look ma, I’m writing with no hands

Imagine being able to type every thought you had without using your hands, the words just magically appearing on the screen as fast as you can think of writing them down. Well, with the help of a new brain-computer interface (BCI), you can.

In a recent paper published in Nature, a team of researchers described how they developed a whole new way of communicating that blows previous BCIs, which used a method of pointing and clicking on letters, out of the water as far as accuracy and speed are concerned.

Developed for individuals with medical conditions or other disabilities that prevent them from communicating verbally or manually, the technology involves placing tiny sensors on the brain in the areas that control hand and arm movements. All the individual has to do is think of the process of writing and the system does the rest.

©Thinkstock

Chicken noodle salmonella

Chickens and ducks sure are cute, especially babies, but humans should be extra careful around these animals for risk of salmonella. This isn’t a new thing to loyal readers of Livin’ on the MDedge.

As more people keep such creatures at home – Emily Shoop of Penn State University told the N.Y. Times that raising poultry was “the fastest-growing animal-related hobby in the United States” – the ducks and chickens are being treated more like house pets, which is sweet but not safe.

In the latest outbreak, more than 160 people, mostly children under 5 years old, have fallen ill from salmonella poisoning and more than 30 have been hospitalized across 43 states, and the Centers for Disease Control and Prevention suspects the numbers could be higher because many did not get tested and recovered on their own.

JasonJiron/Thinkstock

This kidney research rocks!

When kids pick teams on the playground, someone is going to get their feelings hurt by being chosen last. There’s no way around it. Someone has to be last.

It’s the same way with research teams. When scientists are trying to cure diseases or pioneer new surgical techniques, they get a team together. And who always gets picked last? That’s right, the geologist, because who needs a geologist when you’re studying brain-computer interfaces?

Turns out, though, that there was a research team that needed a geologist: The one studying kidney stones.

Illinois geology professor Bruce Fouke explains: “The process of kidney stone formation is part of the natural process of the stone formation seen throughout nature. We are bringing together geology, biology, and medicine to map the entire process of kidney stone formation, step by step.”

Mayandi Sivaguru

Gene therapy: What is it good for? Absolutely nothing!

Gene therapy has the potential to permanently cure all sorts of terrible diseases, and one would assume that this would be something we all could agree on. Yes, no more cancer or diabetes or anything like that, no sane person could possibly be against this, right?

Oh, you poor naive fool.

To be fair, the report written by Goldman Sachs does lay out many potential applications for gene therapy, and all the markets it can expand into. But then the writers ask the question that they’re not supposed to say out loud: Is curing patients a sustainable business model?

Pogonic/Getty Images

Look ma, I’m writing with no hands

Imagine being able to type every thought you had without using your hands, the words just magically appearing on the screen as fast as you can think of writing them down. Well, with the help of a new brain-computer interface (BCI), you can.

In a recent paper published in Nature, a team of researchers described how they developed a whole new way of communicating that blows previous BCIs, which used a method of pointing and clicking on letters, out of the water as far as accuracy and speed are concerned.

Developed for individuals with medical conditions or other disabilities that prevent them from communicating verbally or manually, the technology involves placing tiny sensors on the brain in the areas that control hand and arm movements. All the individual has to do is think of the process of writing and the system does the rest.

©Thinkstock

Chicken noodle salmonella

Chickens and ducks sure are cute, especially babies, but humans should be extra careful around these animals for risk of salmonella. This isn’t a new thing to loyal readers of Livin’ on the MDedge.

As more people keep such creatures at home – Emily Shoop of Penn State University told the N.Y. Times that raising poultry was “the fastest-growing animal-related hobby in the United States” – the ducks and chickens are being treated more like house pets, which is sweet but not safe.

In the latest outbreak, more than 160 people, mostly children under 5 years old, have fallen ill from salmonella poisoning and more than 30 have been hospitalized across 43 states, and the Centers for Disease Control and Prevention suspects the numbers could be higher because many did not get tested and recovered on their own.

JasonJiron/Thinkstock

This kidney research rocks!

When kids pick teams on the playground, someone is going to get their feelings hurt by being chosen last. There’s no way around it. Someone has to be last.

It’s the same way with research teams. When scientists are trying to cure diseases or pioneer new surgical techniques, they get a team together. And who always gets picked last? That’s right, the geologist, because who needs a geologist when you’re studying brain-computer interfaces?

Turns out, though, that there was a research team that needed a geologist: The one studying kidney stones.

Illinois geology professor Bruce Fouke explains: “The process of kidney stone formation is part of the natural process of the stone formation seen throughout nature. We are bringing together geology, biology, and medicine to map the entire process of kidney stone formation, step by step.”

Mayandi Sivaguru

Gene therapy: What is it good for? Absolutely nothing!

Gene therapy has the potential to permanently cure all sorts of terrible diseases, and one would assume that this would be something we all could agree on. Yes, no more cancer or diabetes or anything like that, no sane person could possibly be against this, right?

Oh, you poor naive fool.

To be fair, the report written by Goldman Sachs does lay out many potential applications for gene therapy, and all the markets it can expand into. But then the writers ask the question that they’re not supposed to say out loud: Is curing patients a sustainable business model?

Pogonic/Getty Images

Liver cirrhosis is implicated in 75% to 85% of ascites cases in the Western world, with heart failure or malignancy accounting for fewer cases.¹ Among patients who have decompensated cirrhosis with ascites, annual mortality is 20%.² Another study showed a 3-year survival rate after onset of ascites of only 56%.³ It is vital for primary care physicians (PCPs) to be alert for ascites not only in patients who have risk factors for chronic liver disease and cirrhosis—eg, a history of alcohol use disorder, chronic viral infections (hepatitis B and C), or metabolic syndrome—but also in patients with abnormal liver function tests and thrombocytopenia. In this review, we discuss the initial assessment of ascites and its long-term management, concentrating on the role of the PCP.

Pathophysiology: Vasodilation leads to a cascade

Splanchnic vasodilation is the main underlying event triggering a pathologic cascade that leads to the development of ascites.⁴ Initially portal hypertension in the setting of liver inflammation and fibrosis causes the release of inflammatory cytokines such as nitric oxide and carbon monoxide. This, in turn, causes the pathologic dilation of splanchnic circulation that decreases effective circulating volume. Activation of the sympathetic nervous system, vasopressin, and renin-­angiotensin-aldosterone system (RAAS) then causes the proximal and distal tubules to increase renal absorption of sodium and water.⁵ The resulting volume overload further decreases the heart’s ability to maintain circulating volume, leading to increased activation of compensating symptoms. This vicious cycle eventually manifests as ascites.⁶

A complex interplay of cirrhosis-associated immune dysfunction (CAID), gut dysbiosis, and increased translocation of microorganisms into ascitic fluid is also an important aspect of the pathogenesis.⁷ CAID (FIGURE 1)^7,8 is an immunodeficient state due to cirrhosis with reduced phagocytic activity by neutrophils and macrophages, T- and B-cell hypoproliferation, and reduced cytotoxicity of natural killer cells. In parallel, there is increased production of inflammatory cytokines due to the effects of damage-associated molecular patterns (DAMPs) from hepatocytes and ­pathogen-associated molecular patterns (PAMPs) from the gut microbiota on the immune system, which leads to many of the manifestations of decompensated cirrhosis including ascites.⁸

Key in on these elementsof the history and exam

Each step of the basic work-up for ascites provides opportunities to refine or redirect the diagnostic inquiry (TABLE).

History

Generally, patients with ascites present with weight gain and symptoms of abdominal distension, such as early satiety, nausea, and vomiting. Besides cirrhosis, rule out other causes of ascites, as treatment differs based on the cause.⁹ Also ask about histories of cancer and cardiac, renal, or thyroid disease.¹⁰

Patients with ascites in the setting of liver disease usually are asymptomatic in its early stages. Common complaints are vague abdominal pain, generalized weakness, malaise, and fatigue.¹¹ Ask patients about risk factors for liver disease such as obesity, diabetes, hypertension, alcohol use, unsafe sexual practices, recent travel, and needle sharing or drug use. Due to a strong association between obstructive sleep apnea and fatty liver disease, consider screening at-risk patients for sleep apnea.¹²

Physical exam

When there are risk factors for liver disease, examine the patient for stigmata of cirrhosis and ascites. Signs of liver disease, aside from ascites, may include spider angiomas on the upper trunk (33% of cirrhosis patients),¹³ gynecomastia (44% of cirrhosis patients),¹⁴ palmar erythema, jaundice, asterixis, and abdominal wall collaterals including caput medusa.¹⁵

Continue to: We suggest a systematic...

We suggest a systematic and targeted approach to using various physical exam maneuvers described in the literature. If the patient has a full/distended abdomen, percuss the flanks. If increased dullness at the flanks is detected, check for shifting dullness, which indicates at least 1500 mL of fluid in the abdomen.¹⁶ Keep in mind that a 10% chance of ascites exists even if shifting dullness is absent.¹⁷ Maneuvers such as the puddle sign and fluid thrill are less accurate than shifting dullness, which has 83% sensitivity and 56% specificity in detecting ascites.¹⁷ Patients with cirrhosis also have a high likelihood of complications from ascites such as inguinal, umbilical, and other hernias.

Diagnostic work-up includes blood tests and ultrasound

Blood tests. The initial work-up for ascites should include complete blood count, complete metabolic panel, and prothrombin time/international normalized ratio.¹⁸

Abdominal ultrasound is recommended as the first-line imaging test.¹⁹ Aside from detecting ascites, it can give an estimate of the volume of ascites and indicate whether it is amenable to paracentesis. A vascular exam added to the standard ultrasound can detect radiologic evidence of portal hypertension such as splenomegaly, portosystemic collaterals, splenorenal shunt, patency of the paraumbilical vein, and portal vein diameter. Patients with established cirrhosis also require abdominal ultrasound every 6 months to screen for hepatocellular cancer.²⁰

Abdominal paracentesis is the cornerstone of ascites evaluation.²¹ It is indicated for every patient with new-onset ascites or for any patient with known ascites and clinical deterioration. Ascitic fluid analysis can be used to easily differentiate portal hypertension from other causes of ascites. It can also be used to rule out bacterial peritonitis. The recommended sites for evaluation are in the left lower quadrant, 3 cm cranially and 3 cm medially from the anterior superior iliac spine.²² A large cohort study showed that abdominal ultrasound-guided paracentesis reduced bleeding complications by 68% following the procedure and is strongly recommended (if available).²³ Generally, paracentesis is a relatively safe procedure with a low risk of complications such as abdominal wall hematoma (1%), hemoperitoneum (< 0.1%), bowel perforation (< 0.1%), and infection (< 0.1%).²⁴

Calculating the serum ascites albumin gradient better characterizes ascitic fluid than total protein-based tests.

Assess all ascitic fluid samples for color, consistency, cell count and differential, albumin, and total protein. These tests are usually sufficient to provide evidence regarding the cause of ascites. If there is suspicion of infection, order a gram stain and culture (80% sensitivity for detecting an infection if obtained prior to initiation of antibiotics)²⁵ and glucose, lactate dehydrogenase (useful to differentiate primary from secondary bacterial peritonitis),²⁶ and amylase tests. Other tests such as cytology, acid-fast bacilli smear and culture, and triglyceride level should only be obtained if specific conditions are suspected based on high pretest probabilities.

Continue to: Calculating serum ascites albumin gradient...

Calculating serum ascites albumin gradient (SAAG) is recommended as it has been shown to better characterize ascitic fluid than total protein-based tests.²⁷ SAAG is calculated by subtracting the level of ascitic fluid albumin from serum albumin level (SAAG = serum albumin – ascitic fluid albumin). A SAAG ≥ 1.1 g/dL is consistent with portal hypertension,²⁸ with approximately 97% accuracy.

After calculating SAAG, look at total protein levels in ascitic fluid. Total protein concentration ≥ 2.5 g/dL with SAAG ≥ 1.1 g/dL has a 78.3% diagnostic accuracy in determining heart failure as the cause of ascites, with a sensitivity of 53.3% and specificity of 86.7%.²⁸ On the other hand, a value of total protein < 2.5 g/dL indicates cirrhosis, liver failure, or acute hepatitis as the cause of fluid build-up.²⁹ Stepwise evaluation of SAAG and total protein and how they can point toward the most likely cause of ascites is presented in FIGURE 2.^27-29

Management

Noninvasive measures

Sodium restriction. The aim of treatment for uncomplicated clinically apparent ascites is sodium restriction and removal of fluid from the body. Dietary salt restriction is complicated, and care should be taken to properly educate patients. Salt restriction advised in the literature has shifted from a strict measure of < 2 g/d³⁰ to more moderate strategies (described below).¹⁸

The 2 main reasons for this easing of restriction are issues with patient compliance and concerns about adverse effects with aggressive salt-restricted diets. One study assessing patient compliance with a salt-restricted diet found that more than two-thirds of the patients were noncompliant,³¹ and 65% of the patients incorrectly assumed they were following the plan, which suggests poor dietary education.³¹ Of the group that was compliant, 20% actually decreased their caloric intake, which can be detrimental in liver disease.³¹ Concerns have been raised that aggressive salt restriction along with diuretic use can lead to diuretic-induced hyponatremia and renal failure.³² Current European Association for the Study of the Liver (EASL) guidelines recommend salt restriction to a more moderate degree (80-120 mmol/d of sodium). This is equivalent to 4.9-6.9 g of salt (1 tablespoon is roughly equivalent to 6 g or 104 mmol of sodium).¹⁸

Diuretics. Initiation and dosage of diuretic therapy is a matter of some controversy. Historically, simultaneous ­administration of a loop diuretic and mineralocorticoid receptor blocker were recommended: 40 mg furosemide and 100 mg spironolactone, keeping the ratio constant with any dosage increases. This was based on a randomized controlled trial (RCT) showing that the combined diuretic therapy effectively mobilized ascites in a shorter period of time and with less frequent adverse effects (eg, hyperkalemia) compared with initial monotherapy.³³

Continue to: On the other hand...

On the other hand, another study with more stable patients and relatively normal renal function showed that starting with a mineralocorticoid receptor blocker alone with sequential dose increments had equivalent benefit with no increase in adverse effects.³⁴ Since the patient population in this study was more in line with what a PCP might encounter, we recommend following this guideline initially and keeping a close watch on serum electrolytes.

Usual maximum doses are spironolactone 400 mg/d and furosemide 160 mg/d.^21,35 Adequate weight loss for patients with diffuse edema is at least 1 kg/d, per EASL guidelines.^36,37 However, this might not be practical in outpatient settings, and a more conservative target of 0.5 kg/d may be used for patients without significant edema.³⁷

It is vital to get accurate daily weights and avoid excessive diuretic use, as it has been associated with intravascular volume depletion and acute kidney injury (25%), hyponatremia (28%),^38,39 and hepatic encephalopathy (30%).⁴⁰ Therefore, patients with acute kidney injury, hyponatremia, acute variceal hemorrhage, or infection should also have their diuretics held until their creatinine returns to baseline.

Invasive measures

Large-volume paracentesis. Patients with extensive and tense ascites should be treated initially with large-volume paracentesis, as this has been shown to predictably remove fluid more effectively than diuretics.³⁸ This should be accompanied by albumin administration, 8 g for every liter of ascitic fluid removed if the total amount exceeds 5 L.⁴¹ Following large-volume paracentesis, manage patients with the standard salt restriction and diuretic regimen.³⁸ Serial large-volume paracentesis is a temporary measure reserved for a select group of patients who are intolerant to diuretics and are not candidates for a shunt.

Transjugular intrahepatic portosystemic shunt (TIPS) is another option to control refractory ascites, but its benefit should be weighed against complications such as hepatic encephalopathy. An RCT found that TIPS with covered stents improved survival in patients with cirrhosis compared with regular large-volume paracentesis.⁴² Patients should be referred to hepatologists to make a determination about TIPS placement. Widely accepted contraindications for the placement of TIPS are decompensated cirrhosis (Child-Pugh > 11, model for end-stage liver disease [MELD] > 18), renal failure (serum creatinine > 3 mg/dL), heart failure, porto-pulmonary hypertension, and uncontrolled sepsis.⁴³ Recurrent or persistent hepatic encephalopathy (West Haven grade ≥ 2) is also a contraindication. The West Haven scale is widely used to measure severity of hepatic encephalopathy, grading it from 1 to 4, with 1 being mild encephalopathy characterized by lack of awareness and shorter attention span, and 4 indicating unresponsiveness or coma.⁴⁴

Continue to: How to manage refractory ascites

Fragile patients are those with refractory ascites that is either unresponsive to standard salt restriction and maximum-dose diuretic therapy or that results in a re-accumulation of ascitic fluid soon after paracentesis.⁴⁵ Specialist care is required to improve survival and quality of life for these patients. They should be referred to a hepatologist for consideration of TIPS placement or liver transplantation.¹⁸

Long-term use of albumin was tested in 2 trials for management of decompensated cirrhosis with ascites, yielding conflicting results. The ANSWER trial from Italy showed benefit with this treatment for prolonged survival.⁴⁶ The other trial, from Spain, showed no benefit from albumin and midodrine administration for survival or for improving complications of cirrhosis.⁴⁷ The contradictory results are likely due to heterogeneous populations in the 2 trials and differences in dose and duration of albumin administration. Hence, no clear recommendations can be made based on the available data; further research is needed.

Getting a handle on bacterial peritonitis

Bacterial peritonitis can be divided into spontaneous bacterial peritonitis (SBP) and secondary bacterial peritonitis. SBP is a common complication in patients with cirrhosis and occurs in around 16% of hospitalized patients, based on 1 study.⁴⁸ SBP is defined as a polymorphonuclear leukocyte count ≥ 250 cells/μL in the absence of a surgically treatable source of infection.⁴⁹ It is believed to be caused by bacterial translocation and is treated empirically with a third-­generation cephalosporin. This treatment has been shown to be effective in 85% of patients.⁵⁰

Diuresis with mineralocorticoid inhibitors alone may be considered for new onset mild-to-moderate ascites in patients with normal renal function.

Patients with SBP are at a higher risk for renal impairment, likely resulting from increased cytokine production and decreased circulatory volume.⁵¹ Concomitant albumin administration has been shown to significantly improve outcomes and to reduce rates of hepatorenal syndrome in patients with serum creatinine > 1 mg/dL, blood urea nitrogen > 30 mg/dL, or total bilirubin > 4 mg/dL.⁵² The recommended amount of albumin is 1.5 g/kg given within 6 hours of SBP detection and repeat administration of 1 g/kg on Day 3.⁵²

Guidelines from the American Association for the Study of Liver Diseases and from EASL recommend the long-term use of daily norfloxacin or trimethoprim-­sulfamethoxazole as secondary prophylaxis in patients who have survived an episode of SBP.^18,30 Long-term antibiotic use is also justified for primary prophylaxis in cirrhosis patients who fulfill certain criteria: ascitic fluid protein < 1.5 g/dL along with impaired renal function (serum creatinine ≥ 1.2 mg/dL, blood urea nitrogen ≥ 25 mg/dL, or serum sodium ≥ 130 mEq/L) or with decompensated cirrhosis (Child-Pugh score ≥ 9 and bilirubin ≥ 3 mg/dL).⁵³ It has been shown to reduce the risk of SBP and hepatorenal syndrome, and improve overall survival.⁵³

Continue to: Avoid these medications

Avoid these medications

Commonly used medications that should be avoided in patients with cirrhosis and ascites are angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. These agents block the action of angiotensin, which is a vital vasoconstrictor, and thereby cause a drop in blood pressure. This has independently been associated with poor outcomes in patients with cirrhosis.³⁷

Commonly used medications that should be avoided in patients with cirrhosis and ascites are angiotensin-converting enzyme inhibitors and angiotensin receptor blockers.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are also relatively contraindicated in cirrhosis, as they can affect kidney function, induce azotemia, and reduce kidney sodium excretion. NSAIDs induce vasoconstriction of afferent arterioles in the kidneys, leading to a decreased glomerular filtration rate, further activating RAAS and sympathetic drive. This leads to increased sodium and water retention and worsening ascites.⁵⁴

Improve outcomes by circling in a hepatologist

PCPs can play a vital role in the prevention, treatment, surveillance, and home care of patients with cirrhosis who are at risk for ascites.⁵⁵ Referral of patients with hepatic impairment manifesting as unexplained abnormal liver function tests, new-onset ascites, and/or image findings consistent with cirrhosis to a hepatologist at least once is recommended. Such referrals have been shown to be associated with a better overall outcome.⁵⁶ Patients with known cirrhosis leading to ascites can generally be managed at home with the assistance of specialists and specialized nurses.³⁵

NSAIDs are relatively contraindicated in cirrhosis as they can affect kidney function, induce azotemia, and reduce kidney sodium excretion.

In a study from the University of Michigan, 69% of patients with cirrhosis had at least 1 nonelective readmission; 14% of patients were readmitted within 1 week, and 37% within 1 month.⁵⁷ These are staggering statistics that highlight the gaps in care coordination and management of patients with cirrhosis in the outpatient setting. PCPs can play a vital role in bridging this gap.

A promising framework is suggested by a study from Italy by Morando et al in 2013.⁵⁸ The researchers assessed a specialized health care model for cirrhotic patients and showed significant improvement in health care cost, readmission rate, and overall mortality when compared with the existing model of outpatient care.⁵⁸

Continue to: This was not a blinded study...

This was not a blinded study and there were concerns raised by the scientific community about its design. Because it was conducted in Italy, the results might not be fully applicable to the United States health care setting. However, it did show that better coordination of care leads to significantly better patient outcomes and reduces health care expenditure. Therefore, a more complete understanding of the disease process and latest literature by PCPs, communication with specialists, and comprehensive coordination of care by all parties involved is vital for the management of this patient population.

CORRESPONDENCE
Muhammad Salman Faisal, MD, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195; [email protected]

Liver cirrhosis is implicated in 75% to 85% of ascites cases in the Western world, with heart failure or malignancy accounting for fewer cases.¹ Among patients who have decompensated cirrhosis with ascites, annual mortality is 20%.² Another study showed a 3-year survival rate after onset of ascites of only 56%.³ It is vital for primary care physicians (PCPs) to be alert for ascites not only in patients who have risk factors for chronic liver disease and cirrhosis—eg, a history of alcohol use disorder, chronic viral infections (hepatitis B and C), or metabolic syndrome—but also in patients with abnormal liver function tests and thrombocytopenia. In this review, we discuss the initial assessment of ascites and its long-term management, concentrating on the role of the PCP.

Pathophysiology: Vasodilation leads to a cascade

Splanchnic vasodilation is the main underlying event triggering a pathologic cascade that leads to the development of ascites.⁴ Initially portal hypertension in the setting of liver inflammation and fibrosis causes the release of inflammatory cytokines such as nitric oxide and carbon monoxide. This, in turn, causes the pathologic dilation of splanchnic circulation that decreases effective circulating volume. Activation of the sympathetic nervous system, vasopressin, and renin-­angiotensin-aldosterone system (RAAS) then causes the proximal and distal tubules to increase renal absorption of sodium and water.⁵ The resulting volume overload further decreases the heart’s ability to maintain circulating volume, leading to increased activation of compensating symptoms. This vicious cycle eventually manifests as ascites.⁶

A complex interplay of cirrhosis-associated immune dysfunction (CAID), gut dysbiosis, and increased translocation of microorganisms into ascitic fluid is also an important aspect of the pathogenesis.⁷ CAID (FIGURE 1)^7,8 is an immunodeficient state due to cirrhosis with reduced phagocytic activity by neutrophils and macrophages, T- and B-cell hypoproliferation, and reduced cytotoxicity of natural killer cells. In parallel, there is increased production of inflammatory cytokines due to the effects of damage-associated molecular patterns (DAMPs) from hepatocytes and ­pathogen-associated molecular patterns (PAMPs) from the gut microbiota on the immune system, which leads to many of the manifestations of decompensated cirrhosis including ascites.⁸

Key in on these elementsof the history and exam

Each step of the basic work-up for ascites provides opportunities to refine or redirect the diagnostic inquiry (TABLE).

History

Generally, patients with ascites present with weight gain and symptoms of abdominal distension, such as early satiety, nausea, and vomiting. Besides cirrhosis, rule out other causes of ascites, as treatment differs based on the cause.⁹ Also ask about histories of cancer and cardiac, renal, or thyroid disease.¹⁰

Patients with ascites in the setting of liver disease usually are asymptomatic in its early stages. Common complaints are vague abdominal pain, generalized weakness, malaise, and fatigue.¹¹ Ask patients about risk factors for liver disease such as obesity, diabetes, hypertension, alcohol use, unsafe sexual practices, recent travel, and needle sharing or drug use. Due to a strong association between obstructive sleep apnea and fatty liver disease, consider screening at-risk patients for sleep apnea.¹²

Physical exam

When there are risk factors for liver disease, examine the patient for stigmata of cirrhosis and ascites. Signs of liver disease, aside from ascites, may include spider angiomas on the upper trunk (33% of cirrhosis patients),¹³ gynecomastia (44% of cirrhosis patients),¹⁴ palmar erythema, jaundice, asterixis, and abdominal wall collaterals including caput medusa.¹⁵

Continue to: We suggest a systematic...

We suggest a systematic and targeted approach to using various physical exam maneuvers described in the literature. If the patient has a full/distended abdomen, percuss the flanks. If increased dullness at the flanks is detected, check for shifting dullness, which indicates at least 1500 mL of fluid in the abdomen.¹⁶ Keep in mind that a 10% chance of ascites exists even if shifting dullness is absent.¹⁷ Maneuvers such as the puddle sign and fluid thrill are less accurate than shifting dullness, which has 83% sensitivity and 56% specificity in detecting ascites.¹⁷ Patients with cirrhosis also have a high likelihood of complications from ascites such as inguinal, umbilical, and other hernias.

Diagnostic work-up includes blood tests and ultrasound

Blood tests. The initial work-up for ascites should include complete blood count, complete metabolic panel, and prothrombin time/international normalized ratio.¹⁸

Abdominal ultrasound is recommended as the first-line imaging test.¹⁹ Aside from detecting ascites, it can give an estimate of the volume of ascites and indicate whether it is amenable to paracentesis. A vascular exam added to the standard ultrasound can detect radiologic evidence of portal hypertension such as splenomegaly, portosystemic collaterals, splenorenal shunt, patency of the paraumbilical vein, and portal vein diameter. Patients with established cirrhosis also require abdominal ultrasound every 6 months to screen for hepatocellular cancer.²⁰

Abdominal paracentesis is the cornerstone of ascites evaluation.²¹ It is indicated for every patient with new-onset ascites or for any patient with known ascites and clinical deterioration. Ascitic fluid analysis can be used to easily differentiate portal hypertension from other causes of ascites. It can also be used to rule out bacterial peritonitis. The recommended sites for evaluation are in the left lower quadrant, 3 cm cranially and 3 cm medially from the anterior superior iliac spine.²² A large cohort study showed that abdominal ultrasound-guided paracentesis reduced bleeding complications by 68% following the procedure and is strongly recommended (if available).²³ Generally, paracentesis is a relatively safe procedure with a low risk of complications such as abdominal wall hematoma (1%), hemoperitoneum (< 0.1%), bowel perforation (< 0.1%), and infection (< 0.1%).²⁴

Calculating the serum ascites albumin gradient better characterizes ascitic fluid than total protein-based tests.

Assess all ascitic fluid samples for color, consistency, cell count and differential, albumin, and total protein. These tests are usually sufficient to provide evidence regarding the cause of ascites. If there is suspicion of infection, order a gram stain and culture (80% sensitivity for detecting an infection if obtained prior to initiation of antibiotics)²⁵ and glucose, lactate dehydrogenase (useful to differentiate primary from secondary bacterial peritonitis),²⁶ and amylase tests. Other tests such as cytology, acid-fast bacilli smear and culture, and triglyceride level should only be obtained if specific conditions are suspected based on high pretest probabilities.

Continue to: Calculating serum ascites albumin gradient...

Calculating serum ascites albumin gradient (SAAG) is recommended as it has been shown to better characterize ascitic fluid than total protein-based tests.²⁷ SAAG is calculated by subtracting the level of ascitic fluid albumin from serum albumin level (SAAG = serum albumin – ascitic fluid albumin). A SAAG ≥ 1.1 g/dL is consistent with portal hypertension,²⁸ with approximately 97% accuracy.

After calculating SAAG, look at total protein levels in ascitic fluid. Total protein concentration ≥ 2.5 g/dL with SAAG ≥ 1.1 g/dL has a 78.3% diagnostic accuracy in determining heart failure as the cause of ascites, with a sensitivity of 53.3% and specificity of 86.7%.²⁸ On the other hand, a value of total protein < 2.5 g/dL indicates cirrhosis, liver failure, or acute hepatitis as the cause of fluid build-up.²⁹ Stepwise evaluation of SAAG and total protein and how they can point toward the most likely cause of ascites is presented in FIGURE 2.^27-29

Management

Noninvasive measures

Sodium restriction. The aim of treatment for uncomplicated clinically apparent ascites is sodium restriction and removal of fluid from the body. Dietary salt restriction is complicated, and care should be taken to properly educate patients. Salt restriction advised in the literature has shifted from a strict measure of < 2 g/d³⁰ to more moderate strategies (described below).¹⁸

The 2 main reasons for this easing of restriction are issues with patient compliance and concerns about adverse effects with aggressive salt-restricted diets. One study assessing patient compliance with a salt-restricted diet found that more than two-thirds of the patients were noncompliant,³¹ and 65% of the patients incorrectly assumed they were following the plan, which suggests poor dietary education.³¹ Of the group that was compliant, 20% actually decreased their caloric intake, which can be detrimental in liver disease.³¹ Concerns have been raised that aggressive salt restriction along with diuretic use can lead to diuretic-induced hyponatremia and renal failure.³² Current European Association for the Study of the Liver (EASL) guidelines recommend salt restriction to a more moderate degree (80-120 mmol/d of sodium). This is equivalent to 4.9-6.9 g of salt (1 tablespoon is roughly equivalent to 6 g or 104 mmol of sodium).¹⁸

Diuretics. Initiation and dosage of diuretic therapy is a matter of some controversy. Historically, simultaneous ­administration of a loop diuretic and mineralocorticoid receptor blocker were recommended: 40 mg furosemide and 100 mg spironolactone, keeping the ratio constant with any dosage increases. This was based on a randomized controlled trial (RCT) showing that the combined diuretic therapy effectively mobilized ascites in a shorter period of time and with less frequent adverse effects (eg, hyperkalemia) compared with initial monotherapy.³³

Continue to: On the other hand...

On the other hand, another study with more stable patients and relatively normal renal function showed that starting with a mineralocorticoid receptor blocker alone with sequential dose increments had equivalent benefit with no increase in adverse effects.³⁴ Since the patient population in this study was more in line with what a PCP might encounter, we recommend following this guideline initially and keeping a close watch on serum electrolytes.

Usual maximum doses are spironolactone 400 mg/d and furosemide 160 mg/d.^21,35 Adequate weight loss for patients with diffuse edema is at least 1 kg/d, per EASL guidelines.^36,37 However, this might not be practical in outpatient settings, and a more conservative target of 0.5 kg/d may be used for patients without significant edema.³⁷

It is vital to get accurate daily weights and avoid excessive diuretic use, as it has been associated with intravascular volume depletion and acute kidney injury (25%), hyponatremia (28%),^38,39 and hepatic encephalopathy (30%).⁴⁰ Therefore, patients with acute kidney injury, hyponatremia, acute variceal hemorrhage, or infection should also have their diuretics held until their creatinine returns to baseline.

Invasive measures

Large-volume paracentesis. Patients with extensive and tense ascites should be treated initially with large-volume paracentesis, as this has been shown to predictably remove fluid more effectively than diuretics.³⁸ This should be accompanied by albumin administration, 8 g for every liter of ascitic fluid removed if the total amount exceeds 5 L.⁴¹ Following large-volume paracentesis, manage patients with the standard salt restriction and diuretic regimen.³⁸ Serial large-volume paracentesis is a temporary measure reserved for a select group of patients who are intolerant to diuretics and are not candidates for a shunt.

Transjugular intrahepatic portosystemic shunt (TIPS) is another option to control refractory ascites, but its benefit should be weighed against complications such as hepatic encephalopathy. An RCT found that TIPS with covered stents improved survival in patients with cirrhosis compared with regular large-volume paracentesis.⁴² Patients should be referred to hepatologists to make a determination about TIPS placement. Widely accepted contraindications for the placement of TIPS are decompensated cirrhosis (Child-Pugh > 11, model for end-stage liver disease [MELD] > 18), renal failure (serum creatinine > 3 mg/dL), heart failure, porto-pulmonary hypertension, and uncontrolled sepsis.⁴³ Recurrent or persistent hepatic encephalopathy (West Haven grade ≥ 2) is also a contraindication. The West Haven scale is widely used to measure severity of hepatic encephalopathy, grading it from 1 to 4, with 1 being mild encephalopathy characterized by lack of awareness and shorter attention span, and 4 indicating unresponsiveness or coma.⁴⁴

Continue to: How to manage refractory ascites

Fragile patients are those with refractory ascites that is either unresponsive to standard salt restriction and maximum-dose diuretic therapy or that results in a re-accumulation of ascitic fluid soon after paracentesis.⁴⁵ Specialist care is required to improve survival and quality of life for these patients. They should be referred to a hepatologist for consideration of TIPS placement or liver transplantation.¹⁸

Long-term use of albumin was tested in 2 trials for management of decompensated cirrhosis with ascites, yielding conflicting results. The ANSWER trial from Italy showed benefit with this treatment for prolonged survival.⁴⁶ The other trial, from Spain, showed no benefit from albumin and midodrine administration for survival or for improving complications of cirrhosis.⁴⁷ The contradictory results are likely due to heterogeneous populations in the 2 trials and differences in dose and duration of albumin administration. Hence, no clear recommendations can be made based on the available data; further research is needed.

Getting a handle on bacterial peritonitis

Bacterial peritonitis can be divided into spontaneous bacterial peritonitis (SBP) and secondary bacterial peritonitis. SBP is a common complication in patients with cirrhosis and occurs in around 16% of hospitalized patients, based on 1 study.⁴⁸ SBP is defined as a polymorphonuclear leukocyte count ≥ 250 cells/μL in the absence of a surgically treatable source of infection.⁴⁹ It is believed to be caused by bacterial translocation and is treated empirically with a third-­generation cephalosporin. This treatment has been shown to be effective in 85% of patients.⁵⁰

Diuresis with mineralocorticoid inhibitors alone may be considered for new onset mild-to-moderate ascites in patients with normal renal function.

Patients with SBP are at a higher risk for renal impairment, likely resulting from increased cytokine production and decreased circulatory volume.⁵¹ Concomitant albumin administration has been shown to significantly improve outcomes and to reduce rates of hepatorenal syndrome in patients with serum creatinine > 1 mg/dL, blood urea nitrogen > 30 mg/dL, or total bilirubin > 4 mg/dL.⁵² The recommended amount of albumin is 1.5 g/kg given within 6 hours of SBP detection and repeat administration of 1 g/kg on Day 3.⁵²

Guidelines from the American Association for the Study of Liver Diseases and from EASL recommend the long-term use of daily norfloxacin or trimethoprim-­sulfamethoxazole as secondary prophylaxis in patients who have survived an episode of SBP.^18,30 Long-term antibiotic use is also justified for primary prophylaxis in cirrhosis patients who fulfill certain criteria: ascitic fluid protein < 1.5 g/dL along with impaired renal function (serum creatinine ≥ 1.2 mg/dL, blood urea nitrogen ≥ 25 mg/dL, or serum sodium ≥ 130 mEq/L) or with decompensated cirrhosis (Child-Pugh score ≥ 9 and bilirubin ≥ 3 mg/dL).⁵³ It has been shown to reduce the risk of SBP and hepatorenal syndrome, and improve overall survival.⁵³

Continue to: Avoid these medications

Avoid these medications

Commonly used medications that should be avoided in patients with cirrhosis and ascites are angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. These agents block the action of angiotensin, which is a vital vasoconstrictor, and thereby cause a drop in blood pressure. This has independently been associated with poor outcomes in patients with cirrhosis.³⁷

Commonly used medications that should be avoided in patients with cirrhosis and ascites are angiotensin-converting enzyme inhibitors and angiotensin receptor blockers.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are also relatively contraindicated in cirrhosis, as they can affect kidney function, induce azotemia, and reduce kidney sodium excretion. NSAIDs induce vasoconstriction of afferent arterioles in the kidneys, leading to a decreased glomerular filtration rate, further activating RAAS and sympathetic drive. This leads to increased sodium and water retention and worsening ascites.⁵⁴

Improve outcomes by circling in a hepatologist

PCPs can play a vital role in the prevention, treatment, surveillance, and home care of patients with cirrhosis who are at risk for ascites.⁵⁵ Referral of patients with hepatic impairment manifesting as unexplained abnormal liver function tests, new-onset ascites, and/or image findings consistent with cirrhosis to a hepatologist at least once is recommended. Such referrals have been shown to be associated with a better overall outcome.⁵⁶ Patients with known cirrhosis leading to ascites can generally be managed at home with the assistance of specialists and specialized nurses.³⁵

NSAIDs are relatively contraindicated in cirrhosis as they can affect kidney function, induce azotemia, and reduce kidney sodium excretion.

In a study from the University of Michigan, 69% of patients with cirrhosis had at least 1 nonelective readmission; 14% of patients were readmitted within 1 week, and 37% within 1 month.⁵⁷ These are staggering statistics that highlight the gaps in care coordination and management of patients with cirrhosis in the outpatient setting. PCPs can play a vital role in bridging this gap.

A promising framework is suggested by a study from Italy by Morando et al in 2013.⁵⁸ The researchers assessed a specialized health care model for cirrhotic patients and showed significant improvement in health care cost, readmission rate, and overall mortality when compared with the existing model of outpatient care.⁵⁸

Continue to: This was not a blinded study...

This was not a blinded study and there were concerns raised by the scientific community about its design. Because it was conducted in Italy, the results might not be fully applicable to the United States health care setting. However, it did show that better coordination of care leads to significantly better patient outcomes and reduces health care expenditure. Therefore, a more complete understanding of the disease process and latest literature by PCPs, communication with specialists, and comprehensive coordination of care by all parties involved is vital for the management of this patient population.

CORRESPONDENCE
Muhammad Salman Faisal, MD, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195; [email protected]

Liver cirrhosis is implicated in 75% to 85% of ascites cases in the Western world, with heart failure or malignancy accounting for fewer cases.¹ Among patients who have decompensated cirrhosis with ascites, annual mortality is 20%.² Another study showed a 3-year survival rate after onset of ascites of only 56%.³ It is vital for primary care physicians (PCPs) to be alert for ascites not only in patients who have risk factors for chronic liver disease and cirrhosis—eg, a history of alcohol use disorder, chronic viral infections (hepatitis B and C), or metabolic syndrome—but also in patients with abnormal liver function tests and thrombocytopenia. In this review, we discuss the initial assessment of ascites and its long-term management, concentrating on the role of the PCP.

Pathophysiology: Vasodilation leads to a cascade

Splanchnic vasodilation is the main underlying event triggering a pathologic cascade that leads to the development of ascites.⁴ Initially portal hypertension in the setting of liver inflammation and fibrosis causes the release of inflammatory cytokines such as nitric oxide and carbon monoxide. This, in turn, causes the pathologic dilation of splanchnic circulation that decreases effective circulating volume. Activation of the sympathetic nervous system, vasopressin, and renin-­angiotensin-aldosterone system (RAAS) then causes the proximal and distal tubules to increase renal absorption of sodium and water.⁵ The resulting volume overload further decreases the heart’s ability to maintain circulating volume, leading to increased activation of compensating symptoms. This vicious cycle eventually manifests as ascites.⁶

A complex interplay of cirrhosis-associated immune dysfunction (CAID), gut dysbiosis, and increased translocation of microorganisms into ascitic fluid is also an important aspect of the pathogenesis.⁷ CAID (FIGURE 1)^7,8 is an immunodeficient state due to cirrhosis with reduced phagocytic activity by neutrophils and macrophages, T- and B-cell hypoproliferation, and reduced cytotoxicity of natural killer cells. In parallel, there is increased production of inflammatory cytokines due to the effects of damage-associated molecular patterns (DAMPs) from hepatocytes and ­pathogen-associated molecular patterns (PAMPs) from the gut microbiota on the immune system, which leads to many of the manifestations of decompensated cirrhosis including ascites.⁸

Key in on these elementsof the history and exam

Each step of the basic work-up for ascites provides opportunities to refine or redirect the diagnostic inquiry (TABLE).

History

Generally, patients with ascites present with weight gain and symptoms of abdominal distension, such as early satiety, nausea, and vomiting. Besides cirrhosis, rule out other causes of ascites, as treatment differs based on the cause.⁹ Also ask about histories of cancer and cardiac, renal, or thyroid disease.¹⁰

Patients with ascites in the setting of liver disease usually are asymptomatic in its early stages. Common complaints are vague abdominal pain, generalized weakness, malaise, and fatigue.¹¹ Ask patients about risk factors for liver disease such as obesity, diabetes, hypertension, alcohol use, unsafe sexual practices, recent travel, and needle sharing or drug use. Due to a strong association between obstructive sleep apnea and fatty liver disease, consider screening at-risk patients for sleep apnea.¹²

Physical exam

When there are risk factors for liver disease, examine the patient for stigmata of cirrhosis and ascites. Signs of liver disease, aside from ascites, may include spider angiomas on the upper trunk (33% of cirrhosis patients),¹³ gynecomastia (44% of cirrhosis patients),¹⁴ palmar erythema, jaundice, asterixis, and abdominal wall collaterals including caput medusa.¹⁵

Continue to: We suggest a systematic...

We suggest a systematic and targeted approach to using various physical exam maneuvers described in the literature. If the patient has a full/distended abdomen, percuss the flanks. If increased dullness at the flanks is detected, check for shifting dullness, which indicates at least 1500 mL of fluid in the abdomen.¹⁶ Keep in mind that a 10% chance of ascites exists even if shifting dullness is absent.¹⁷ Maneuvers such as the puddle sign and fluid thrill are less accurate than shifting dullness, which has 83% sensitivity and 56% specificity in detecting ascites.¹⁷ Patients with cirrhosis also have a high likelihood of complications from ascites such as inguinal, umbilical, and other hernias.

Diagnostic work-up includes blood tests and ultrasound

Blood tests. The initial work-up for ascites should include complete blood count, complete metabolic panel, and prothrombin time/international normalized ratio.¹⁸

Abdominal ultrasound is recommended as the first-line imaging test.¹⁹ Aside from detecting ascites, it can give an estimate of the volume of ascites and indicate whether it is amenable to paracentesis. A vascular exam added to the standard ultrasound can detect radiologic evidence of portal hypertension such as splenomegaly, portosystemic collaterals, splenorenal shunt, patency of the paraumbilical vein, and portal vein diameter. Patients with established cirrhosis also require abdominal ultrasound every 6 months to screen for hepatocellular cancer.²⁰

Abdominal paracentesis is the cornerstone of ascites evaluation.²¹ It is indicated for every patient with new-onset ascites or for any patient with known ascites and clinical deterioration. Ascitic fluid analysis can be used to easily differentiate portal hypertension from other causes of ascites. It can also be used to rule out bacterial peritonitis. The recommended sites for evaluation are in the left lower quadrant, 3 cm cranially and 3 cm medially from the anterior superior iliac spine.²² A large cohort study showed that abdominal ultrasound-guided paracentesis reduced bleeding complications by 68% following the procedure and is strongly recommended (if available).²³ Generally, paracentesis is a relatively safe procedure with a low risk of complications such as abdominal wall hematoma (1%), hemoperitoneum (< 0.1%), bowel perforation (< 0.1%), and infection (< 0.1%).²⁴

Calculating the serum ascites albumin gradient better characterizes ascitic fluid than total protein-based tests.

Assess all ascitic fluid samples for color, consistency, cell count and differential, albumin, and total protein. These tests are usually sufficient to provide evidence regarding the cause of ascites. If there is suspicion of infection, order a gram stain and culture (80% sensitivity for detecting an infection if obtained prior to initiation of antibiotics)²⁵ and glucose, lactate dehydrogenase (useful to differentiate primary from secondary bacterial peritonitis),²⁶ and amylase tests. Other tests such as cytology, acid-fast bacilli smear and culture, and triglyceride level should only be obtained if specific conditions are suspected based on high pretest probabilities.

Continue to: Calculating serum ascites albumin gradient...

Calculating serum ascites albumin gradient (SAAG) is recommended as it has been shown to better characterize ascitic fluid than total protein-based tests.²⁷ SAAG is calculated by subtracting the level of ascitic fluid albumin from serum albumin level (SAAG = serum albumin – ascitic fluid albumin). A SAAG ≥ 1.1 g/dL is consistent with portal hypertension,²⁸ with approximately 97% accuracy.

After calculating SAAG, look at total protein levels in ascitic fluid. Total protein concentration ≥ 2.5 g/dL with SAAG ≥ 1.1 g/dL has a 78.3% diagnostic accuracy in determining heart failure as the cause of ascites, with a sensitivity of 53.3% and specificity of 86.7%.²⁸ On the other hand, a value of total protein < 2.5 g/dL indicates cirrhosis, liver failure, or acute hepatitis as the cause of fluid build-up.²⁹ Stepwise evaluation of SAAG and total protein and how they can point toward the most likely cause of ascites is presented in FIGURE 2.^27-29

Management

Noninvasive measures

Sodium restriction. The aim of treatment for uncomplicated clinically apparent ascites is sodium restriction and removal of fluid from the body. Dietary salt restriction is complicated, and care should be taken to properly educate patients. Salt restriction advised in the literature has shifted from a strict measure of < 2 g/d³⁰ to more moderate strategies (described below).¹⁸

The 2 main reasons for this easing of restriction are issues with patient compliance and concerns about adverse effects with aggressive salt-restricted diets. One study assessing patient compliance with a salt-restricted diet found that more than two-thirds of the patients were noncompliant,³¹ and 65% of the patients incorrectly assumed they were following the plan, which suggests poor dietary education.³¹ Of the group that was compliant, 20% actually decreased their caloric intake, which can be detrimental in liver disease.³¹ Concerns have been raised that aggressive salt restriction along with diuretic use can lead to diuretic-induced hyponatremia and renal failure.³² Current European Association for the Study of the Liver (EASL) guidelines recommend salt restriction to a more moderate degree (80-120 mmol/d of sodium). This is equivalent to 4.9-6.9 g of salt (1 tablespoon is roughly equivalent to 6 g or 104 mmol of sodium).¹⁸

Diuretics. Initiation and dosage of diuretic therapy is a matter of some controversy. Historically, simultaneous ­administration of a loop diuretic and mineralocorticoid receptor blocker were recommended: 40 mg furosemide and 100 mg spironolactone, keeping the ratio constant with any dosage increases. This was based on a randomized controlled trial (RCT) showing that the combined diuretic therapy effectively mobilized ascites in a shorter period of time and with less frequent adverse effects (eg, hyperkalemia) compared with initial monotherapy.³³

Continue to: On the other hand...

On the other hand, another study with more stable patients and relatively normal renal function showed that starting with a mineralocorticoid receptor blocker alone with sequential dose increments had equivalent benefit with no increase in adverse effects.³⁴ Since the patient population in this study was more in line with what a PCP might encounter, we recommend following this guideline initially and keeping a close watch on serum electrolytes.

Usual maximum doses are spironolactone 400 mg/d and furosemide 160 mg/d.^21,35 Adequate weight loss for patients with diffuse edema is at least 1 kg/d, per EASL guidelines.^36,37 However, this might not be practical in outpatient settings, and a more conservative target of 0.5 kg/d may be used for patients without significant edema.³⁷

It is vital to get accurate daily weights and avoid excessive diuretic use, as it has been associated with intravascular volume depletion and acute kidney injury (25%), hyponatremia (28%),^38,39 and hepatic encephalopathy (30%).⁴⁰ Therefore, patients with acute kidney injury, hyponatremia, acute variceal hemorrhage, or infection should also have their diuretics held until their creatinine returns to baseline.

Invasive measures

Large-volume paracentesis. Patients with extensive and tense ascites should be treated initially with large-volume paracentesis, as this has been shown to predictably remove fluid more effectively than diuretics.³⁸ This should be accompanied by albumin administration, 8 g for every liter of ascitic fluid removed if the total amount exceeds 5 L.⁴¹ Following large-volume paracentesis, manage patients with the standard salt restriction and diuretic regimen.³⁸ Serial large-volume paracentesis is a temporary measure reserved for a select group of patients who are intolerant to diuretics and are not candidates for a shunt.

Transjugular intrahepatic portosystemic shunt (TIPS) is another option to control refractory ascites, but its benefit should be weighed against complications such as hepatic encephalopathy. An RCT found that TIPS with covered stents improved survival in patients with cirrhosis compared with regular large-volume paracentesis.⁴² Patients should be referred to hepatologists to make a determination about TIPS placement. Widely accepted contraindications for the placement of TIPS are decompensated cirrhosis (Child-Pugh > 11, model for end-stage liver disease [MELD] > 18), renal failure (serum creatinine > 3 mg/dL), heart failure, porto-pulmonary hypertension, and uncontrolled sepsis.⁴³ Recurrent or persistent hepatic encephalopathy (West Haven grade ≥ 2) is also a contraindication. The West Haven scale is widely used to measure severity of hepatic encephalopathy, grading it from 1 to 4, with 1 being mild encephalopathy characterized by lack of awareness and shorter attention span, and 4 indicating unresponsiveness or coma.⁴⁴

Continue to: How to manage refractory ascites

Fragile patients are those with refractory ascites that is either unresponsive to standard salt restriction and maximum-dose diuretic therapy or that results in a re-accumulation of ascitic fluid soon after paracentesis.⁴⁵ Specialist care is required to improve survival and quality of life for these patients. They should be referred to a hepatologist for consideration of TIPS placement or liver transplantation.¹⁸

Long-term use of albumin was tested in 2 trials for management of decompensated cirrhosis with ascites, yielding conflicting results. The ANSWER trial from Italy showed benefit with this treatment for prolonged survival.⁴⁶ The other trial, from Spain, showed no benefit from albumin and midodrine administration for survival or for improving complications of cirrhosis.⁴⁷ The contradictory results are likely due to heterogeneous populations in the 2 trials and differences in dose and duration of albumin administration. Hence, no clear recommendations can be made based on the available data; further research is needed.

Getting a handle on bacterial peritonitis

Bacterial peritonitis can be divided into spontaneous bacterial peritonitis (SBP) and secondary bacterial peritonitis. SBP is a common complication in patients with cirrhosis and occurs in around 16% of hospitalized patients, based on 1 study.⁴⁸ SBP is defined as a polymorphonuclear leukocyte count ≥ 250 cells/μL in the absence of a surgically treatable source of infection.⁴⁹ It is believed to be caused by bacterial translocation and is treated empirically with a third-­generation cephalosporin. This treatment has been shown to be effective in 85% of patients.⁵⁰

Diuresis with mineralocorticoid inhibitors alone may be considered for new onset mild-to-moderate ascites in patients with normal renal function.

Patients with SBP are at a higher risk for renal impairment, likely resulting from increased cytokine production and decreased circulatory volume.⁵¹ Concomitant albumin administration has been shown to significantly improve outcomes and to reduce rates of hepatorenal syndrome in patients with serum creatinine > 1 mg/dL, blood urea nitrogen > 30 mg/dL, or total bilirubin > 4 mg/dL.⁵² The recommended amount of albumin is 1.5 g/kg given within 6 hours of SBP detection and repeat administration of 1 g/kg on Day 3.⁵²

Guidelines from the American Association for the Study of Liver Diseases and from EASL recommend the long-term use of daily norfloxacin or trimethoprim-­sulfamethoxazole as secondary prophylaxis in patients who have survived an episode of SBP.^18,30 Long-term antibiotic use is also justified for primary prophylaxis in cirrhosis patients who fulfill certain criteria: ascitic fluid protein < 1.5 g/dL along with impaired renal function (serum creatinine ≥ 1.2 mg/dL, blood urea nitrogen ≥ 25 mg/dL, or serum sodium ≥ 130 mEq/L) or with decompensated cirrhosis (Child-Pugh score ≥ 9 and bilirubin ≥ 3 mg/dL).⁵³ It has been shown to reduce the risk of SBP and hepatorenal syndrome, and improve overall survival.⁵³

Continue to: Avoid these medications

Avoid these medications

Commonly used medications that should be avoided in patients with cirrhosis and ascites are angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. These agents block the action of angiotensin, which is a vital vasoconstrictor, and thereby cause a drop in blood pressure. This has independently been associated with poor outcomes in patients with cirrhosis.³⁷

Commonly used medications that should be avoided in patients with cirrhosis and ascites are angiotensin-converting enzyme inhibitors and angiotensin receptor blockers.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are also relatively contraindicated in cirrhosis, as they can affect kidney function, induce azotemia, and reduce kidney sodium excretion. NSAIDs induce vasoconstriction of afferent arterioles in the kidneys, leading to a decreased glomerular filtration rate, further activating RAAS and sympathetic drive. This leads to increased sodium and water retention and worsening ascites.⁵⁴

Improve outcomes by circling in a hepatologist

PCPs can play a vital role in the prevention, treatment, surveillance, and home care of patients with cirrhosis who are at risk for ascites.⁵⁵ Referral of patients with hepatic impairment manifesting as unexplained abnormal liver function tests, new-onset ascites, and/or image findings consistent with cirrhosis to a hepatologist at least once is recommended. Such referrals have been shown to be associated with a better overall outcome.⁵⁶ Patients with known cirrhosis leading to ascites can generally be managed at home with the assistance of specialists and specialized nurses.³⁵

NSAIDs are relatively contraindicated in cirrhosis as they can affect kidney function, induce azotemia, and reduce kidney sodium excretion.

In a study from the University of Michigan, 69% of patients with cirrhosis had at least 1 nonelective readmission; 14% of patients were readmitted within 1 week, and 37% within 1 month.⁵⁷ These are staggering statistics that highlight the gaps in care coordination and management of patients with cirrhosis in the outpatient setting. PCPs can play a vital role in bridging this gap.

A promising framework is suggested by a study from Italy by Morando et al in 2013.⁵⁸ The researchers assessed a specialized health care model for cirrhotic patients and showed significant improvement in health care cost, readmission rate, and overall mortality when compared with the existing model of outpatient care.⁵⁸

Continue to: This was not a blinded study...

This was not a blinded study and there were concerns raised by the scientific community about its design. Because it was conducted in Italy, the results might not be fully applicable to the United States health care setting. However, it did show that better coordination of care leads to significantly better patient outcomes and reduces health care expenditure. Therefore, a more complete understanding of the disease process and latest literature by PCPs, communication with specialists, and comprehensive coordination of care by all parties involved is vital for the management of this patient population.

CORRESPONDENCE
Muhammad Salman Faisal, MD, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195; [email protected]

The decision to perform a spinal tap procedure in infants to determine whether they have bacterial meningitis should not be guided by abnormal urinalysis results alone, according to new research published in JAMA Network Open.

The findings suggest febrile infants with positive urinalysis results do not have a higher risk of bacterial meningitis than those with negative urinalysis results.

Nearly 1 in 100,000 people are diagnosed with bacterial meningitis in the United States each year, according to Boston Children’s Hospital. Infants have an increased risk for bacterial meningitis, compared with those in other age groups, according to the Centers for Disease Control and Prevention. However, rates of the infectious disease have been declining in the United States since the late 1990s.

Researchers of the current study said published guidelines and quality initiatives recommend performing a lumbar puncture on febrile infants with positive urinalysis results to exclude bacterial meningitis as a cause.

“It really raises the question of should we be doing everything we’re doing?” study author Brett Burstein, MD, PhD, MPH, said in an interview. “What we conclude here is that, contrary to all the published guidelines, this invasive strategy for testing in well-appearing infants should not be guided by the urinalysis results. That’s a major departure.”

The study adds to growing research that questions whether a lumbar puncture in infants with fever and a positive urinalysis results should be routinely required.

“[Our findings] certainly goes against 30 years of clinical decisions, rules, and guidelines,” Dr. Burstein said. “We think they’re very important and they stand to change practice because approximately 500 infants will undergo these invasive procedures to not miss that needle in the haystack.”

Dr. Burstein, a clinician-scientist in pediatric emergency medicine at Montreal Children’s Hospital, led a team of researchers to perform a meta-analysis of 48 studies, including data from more than 25,000 infants.

Researchers found that the prevalence of bacterial meningitis in well-appearing febrile infants aged 29-60 days with a positive urinalysis results was 0.44%, compared with 0.50% of infants with negative urinalysis results.

Instead of relying on urinalysis results alone, Dr. Burstein suggests doctors use other stratifying biomarkers to decide whether they should perform a lumbar puncture.

“If you’ve done blood testing, for example, and your blood test results suggest serious infection, that should guide the decision to go on to invasive testing,” Dr. Burstein said. “You can use your urinary tract infection information in combination now with blood results.”

This means that, if infants have reassuring blood results, despite having a urinary tract infection, they do not need invasive testing, according to Dr. Burstein.

Some of the risks involved with invasive lumbar puncture testing include infection, bleeding, respiratory problems, as well as pain for the infant and parental anxiety.

Paul Aronson, MD, MHS, of Yale University, New Haven, Conn., who was not involved in the study, said in an interview that he has personally moved away from routine lumbar puncture in infants with a positive urinalysis, but added that many doctors have not.

Dr. Aronson said that, although there have been previous studies on this topic, what sets Dr. Burstein’s study apart is the fact that it has a “tightly defined” group of patients, which are infants aged between 29 and 60 days. He also said it is helpful that the study compared the prevalence of meningitis between infants who had positive urinalysis results with those who had negative results.

“The study compared positive urinalyses to negative analyses, which in the meta-analysis form had not been done previously,” Dr. Aronson said. “And so I think this [current study] probably provides some of the strongest evidence.”

No relevant financial relationships were reported.

The decision to perform a spinal tap procedure in infants to determine whether they have bacterial meningitis should not be guided by abnormal urinalysis results alone, according to new research published in JAMA Network Open.

The findings suggest febrile infants with positive urinalysis results do not have a higher risk of bacterial meningitis than those with negative urinalysis results.

Nearly 1 in 100,000 people are diagnosed with bacterial meningitis in the United States each year, according to Boston Children’s Hospital. Infants have an increased risk for bacterial meningitis, compared with those in other age groups, according to the Centers for Disease Control and Prevention. However, rates of the infectious disease have been declining in the United States since the late 1990s.

Researchers of the current study said published guidelines and quality initiatives recommend performing a lumbar puncture on febrile infants with positive urinalysis results to exclude bacterial meningitis as a cause.

“It really raises the question of should we be doing everything we’re doing?” study author Brett Burstein, MD, PhD, MPH, said in an interview. “What we conclude here is that, contrary to all the published guidelines, this invasive strategy for testing in well-appearing infants should not be guided by the urinalysis results. That’s a major departure.”

The study adds to growing research that questions whether a lumbar puncture in infants with fever and a positive urinalysis results should be routinely required.

“[Our findings] certainly goes against 30 years of clinical decisions, rules, and guidelines,” Dr. Burstein said. “We think they’re very important and they stand to change practice because approximately 500 infants will undergo these invasive procedures to not miss that needle in the haystack.”

Dr. Burstein, a clinician-scientist in pediatric emergency medicine at Montreal Children’s Hospital, led a team of researchers to perform a meta-analysis of 48 studies, including data from more than 25,000 infants.

Researchers found that the prevalence of bacterial meningitis in well-appearing febrile infants aged 29-60 days with a positive urinalysis results was 0.44%, compared with 0.50% of infants with negative urinalysis results.

Instead of relying on urinalysis results alone, Dr. Burstein suggests doctors use other stratifying biomarkers to decide whether they should perform a lumbar puncture.

“If you’ve done blood testing, for example, and your blood test results suggest serious infection, that should guide the decision to go on to invasive testing,” Dr. Burstein said. “You can use your urinary tract infection information in combination now with blood results.”

This means that, if infants have reassuring blood results, despite having a urinary tract infection, they do not need invasive testing, according to Dr. Burstein.

Some of the risks involved with invasive lumbar puncture testing include infection, bleeding, respiratory problems, as well as pain for the infant and parental anxiety.

Paul Aronson, MD, MHS, of Yale University, New Haven, Conn., who was not involved in the study, said in an interview that he has personally moved away from routine lumbar puncture in infants with a positive urinalysis, but added that many doctors have not.

Dr. Aronson said that, although there have been previous studies on this topic, what sets Dr. Burstein’s study apart is the fact that it has a “tightly defined” group of patients, which are infants aged between 29 and 60 days. He also said it is helpful that the study compared the prevalence of meningitis between infants who had positive urinalysis results with those who had negative results.

“The study compared positive urinalyses to negative analyses, which in the meta-analysis form had not been done previously,” Dr. Aronson said. “And so I think this [current study] probably provides some of the strongest evidence.”

No relevant financial relationships were reported.

The decision to perform a spinal tap procedure in infants to determine whether they have bacterial meningitis should not be guided by abnormal urinalysis results alone, according to new research published in JAMA Network Open.

The findings suggest febrile infants with positive urinalysis results do not have a higher risk of bacterial meningitis than those with negative urinalysis results.

Nearly 1 in 100,000 people are diagnosed with bacterial meningitis in the United States each year, according to Boston Children’s Hospital. Infants have an increased risk for bacterial meningitis, compared with those in other age groups, according to the Centers for Disease Control and Prevention. However, rates of the infectious disease have been declining in the United States since the late 1990s.

Researchers of the current study said published guidelines and quality initiatives recommend performing a lumbar puncture on febrile infants with positive urinalysis results to exclude bacterial meningitis as a cause.

“It really raises the question of should we be doing everything we’re doing?” study author Brett Burstein, MD, PhD, MPH, said in an interview. “What we conclude here is that, contrary to all the published guidelines, this invasive strategy for testing in well-appearing infants should not be guided by the urinalysis results. That’s a major departure.”

The study adds to growing research that questions whether a lumbar puncture in infants with fever and a positive urinalysis results should be routinely required.

“[Our findings] certainly goes against 30 years of clinical decisions, rules, and guidelines,” Dr. Burstein said. “We think they’re very important and they stand to change practice because approximately 500 infants will undergo these invasive procedures to not miss that needle in the haystack.”

Dr. Burstein, a clinician-scientist in pediatric emergency medicine at Montreal Children’s Hospital, led a team of researchers to perform a meta-analysis of 48 studies, including data from more than 25,000 infants.

Researchers found that the prevalence of bacterial meningitis in well-appearing febrile infants aged 29-60 days with a positive urinalysis results was 0.44%, compared with 0.50% of infants with negative urinalysis results.

Instead of relying on urinalysis results alone, Dr. Burstein suggests doctors use other stratifying biomarkers to decide whether they should perform a lumbar puncture.

“If you’ve done blood testing, for example, and your blood test results suggest serious infection, that should guide the decision to go on to invasive testing,” Dr. Burstein said. “You can use your urinary tract infection information in combination now with blood results.”

This means that, if infants have reassuring blood results, despite having a urinary tract infection, they do not need invasive testing, according to Dr. Burstein.

Some of the risks involved with invasive lumbar puncture testing include infection, bleeding, respiratory problems, as well as pain for the infant and parental anxiety.

Paul Aronson, MD, MHS, of Yale University, New Haven, Conn., who was not involved in the study, said in an interview that he has personally moved away from routine lumbar puncture in infants with a positive urinalysis, but added that many doctors have not.

Dr. Aronson said that, although there have been previous studies on this topic, what sets Dr. Burstein’s study apart is the fact that it has a “tightly defined” group of patients, which are infants aged between 29 and 60 days. He also said it is helpful that the study compared the prevalence of meningitis between infants who had positive urinalysis results with those who had negative results.

“The study compared positive urinalyses to negative analyses, which in the meta-analysis form had not been done previously,” Dr. Aronson said. “And so I think this [current study] probably provides some of the strongest evidence.”

No relevant financial relationships were reported.

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

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

Courtesy American College of Cardiology

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

A former ‘hot concept’

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

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

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

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

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

Denervation coupled with a single, daily three-drug pill

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

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

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

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

But each method has its advantages, he added.

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

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

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

[email protected]

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

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

Courtesy American College of Cardiology

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

A former ‘hot concept’

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

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

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

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

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

Denervation coupled with a single, daily three-drug pill

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

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

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

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

But each method has its advantages, he added.

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

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

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

[email protected]

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

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

Courtesy American College of Cardiology

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

A former ‘hot concept’

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

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

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

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

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

Denervation coupled with a single, daily three-drug pill

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

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

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

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

But each method has its advantages, he added.

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

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

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

[email protected]

Since the last Practice Alert update on recommendations made by the US Preventive Services Task Force,¹ the Task Force has completed work on 12 topics (TABLE 1).^2-17 Five of these topics have been discussed in JFP audio recordings, and the links are provided in TABLE 1.

This latest Task Force endeavor resulted in 18 recommendations (TABLE 2), all of which reaffirm previous recommendations on these topics and expand the scope of 2. There were 2 “A” recommendations, 6 “B” recommendations, 2 “D” recommendations, and 8 “I” statements, indicating that there was insufficient evidence to assess effectiveness or harms. The willingness to make “I” statements when there is little or no evidence on the intervention being assessed distinguishes the USPSTF from other clinical guideline committees.

Screening for carotid artery stenosis

One of the “D” recommendations this past year reaffirms the prior recommendation against screening for carotid artery stenosis in asymptomatic adults—ie, those without a history of transient ischemic attack, stroke, or neurologic signs or symptoms that might be caused by carotid artery stenosis.² The screening tests the Task Force researched included carotid duplex ultrasonography (DUS), magnetic resonance angiography, and computed tomography angiography. The Task Force did not look at the value of auscultation for carotid bruits because it has been proven to be inaccurate and they do not consider it to be a useful screening tool. 

The Task Force based its “D” recommendation on a lack of evidence for any benefit in detecting asymptomatic carotid artery stenosis, and on evidence that screening can lead to harms through false-positive tests and potential complications from carotid endarterectomy and carotid artery angioplasty and stenting. In its clinical considerations, the Task Force emphasized the primary prevention of atherosclerotic disease by focusing on the following actions:

• screening for high blood pressure in adults
• encouraging tobacco smoking cessation in adults
• promoting a healthy diet and physical activity in adults with cardiovascular risk factors
• recommending aspirin use to prevent cardiovascular disease and colorectal cancer
• advising statin use for the primary prevention of cardiovascular disease in adults ages 45 to 75 years who have 1 or more risk factors (hyperlipidemia, diabetes, hypertension, smoking) and those with a 10-year risk of a cardiovascular event of 10% or greater.

This “D” recommendation differs from recommendations made by other professional organizations, some of which recommend testing with DUS for asymptomatic patients with a carotid bruit, and others that recommend DUS screening in patients with multiple risk factors for stroke and in those with known peripheral artery disease or other cardiovascular disease.^18,19

Smoking cessation in adults

Smoking tobacco is the leading preventable cause of death in the United States, causing about 480,000 deaths annually.³ Smoking during pregnancy increases the risk of complications including miscarriage, congenital anomalies, stillbirth, fetal growth restriction, preterm birth, and placental abruption.

The Task Force published recommendations earlier this year advising all clinicians to ask all adult patients about tobacco use; and, for those who smoke, to provide (or refer them to) smoking cessation behavioral therapy. The Task Force also recommends prescribing pharmacotherapy approved by the Food and Drug Administration (FDA) for smoking cessation for nonpregnant adults. (There is a lack of information to assess the harms and benefits of smoking cessation pharmacotherapy during pregnancy.)

Continue to: FDA-approved medications...

The Task Force recommends prescribing pharmacotherapy approved by the FDA for smoking cessation for nonpregnant adults.

FDA-approved medications for treating tobacco smoking dependence are nicotine replacement therapy (NRT), bupropion hydrochloride, and varenicline.³ NRT is available in transdermal patches, lozenges, gum, inhalers, and nasal sprays.

In addition, the Task Force indicates that there is insufficient evidence to assess the benefits and harms of e-cigarettes when used as a method of achieving smoking cessation: “Few randomized trials have evaluated the effectiveness of e-cigarettes to increase tobacco smoking cessation in nonpregnant adults, and no trials have evaluated e-­cigarettes for tobacco smoking cessation in pregnant persons.”⁴

Hepatitis B infection screening

The Task Force reaffirmed a previous recommendation to screen for hepatitis B virus (HBV) infection only in adults who are at high risk,⁵ rather than universal screening that it recommends for hepatitis C virus infection (HCV).⁷ (See: https://bit.ly/3tt064Q). The Task Force has a separate recommendation to screen all pregnant women for hepatitis B at the first prenatal visit.⁶

Those at high risk for hepatitis B who should be screened include individuals born in countries or regions of the world with a hepatitis B surface antigen (HBsAg) prevalence ≥ 2% and individuals born in the United States who have not received HBV vaccine and whose parents were born in regions with an HBsAg prevalence ≥ 8%.⁵ (A table listing countries with HBsAg ≥ 8%—as well as those in lower prevalence categories—is included with the recommendation.⁵)

Screening individuals at high risk for HBV infection is important because nearly two-thirds of those infected are unaware of their condition.

HBV screening should also be offered to other high-risk groups that have a prevalence of positive HBsAg ≥ 2%: those who have injected drugs in the past or are currently injecting drugs; men who have sex with men; individuals with HIV; and sex partners, needle-sharing contacts, and household contacts of people known to be HBsAg positive.⁵

Continue to: It is estimated that...

It is estimated that > 860,000 people in the United States have chronic HBV infection and that close to two-thirds of them are unaware of their infection.⁵ The screening test for HBV is highly accurate; sensitivity and specificity are both > 98%.⁵ While there is no direct evidence that screening, detecting, and treating asymptomatic HBV infection reduces morbidity and mortality, the Task Force felt that the evidence for improvement in multiple outcomes in those with HBV when treated with antiviral regimens was sufficient to support the recommendation.

Screening for bacterial vaginosis in pregnancy

While bacterial vaginosis (BV) is associated with a two-fold risk of preterm delivery, treating BV during pregnancy does not seem to reduce this risk, indicating that some other variable is involved.⁸ In addition, studies that looked at screening for, and treatment of, ­asymptomatic BV in pregnant women at high risk for preterm delivery (defined primarily as those with a previous preterm delivery) have shown inconsistent results. There is the potential for harm in treating BV in pregnancy, chiefly involving gastrointestinal upset caused by metronidazole or clindamycin.

Given that there are no benefits—and some harms—resulting from treatment, the Task Force recommends against screening for BV in non-high-risk pregnant women. A lack of sufficient information to assess any potential benefits to screening in high-risk pregnancies led the Task Force to an “I” statement on this question.⁸

Behavioral counseling on healthy diet, exercise for adults with CV risks

Cardiovascular disease (CVD) remains the number one cause of death in the United States. The major risk factors for CVD, which can be modified, are high blood pressure, hyperlipidemia, diabetes, smoking, obesity or overweight, and lack of physical activity.

The Task Force has previously recommended intensive behavioral interventions to improve nutrition and physical activity in those who are overweight/obese and in those with abnormal blood glucose levels,⁹ and has addressed smoking prevention and cessation.⁴ This new recommendation applies to those with other CVD risks such as high blood pressure and/or hyperlipidemia and those with an estimated 10-year CVD risk of ≥ 7.5%.¹⁰

Continue to: Behavioral interventions...

Behavioral interventions included in the Task Force analysis employed a median of 12 contacts and an estimated 6 hours of contact time over 6 to 18 months.¹⁰ Most interventions involved motivational interviewing and instruction on behavioral change methods. These interventions can be provided by primary care clinicians, as well as a wide range of other trained professionals. The Affordable Care Act dictates that all “A” and “B” recommendations must be provided by commercial health plans at no out-of-pocket expense for the patient.

Nutritional advice should include reductions in saturated fats, salt, and sugars and increases in fruits, vegetables, and whole grains. The Mediterranean diet and the Dietary Approaches to Stop Hypertension (DASH) diet are often recommended.¹⁰ Physical activity counseling should advocate for 90 to 180 minutes per week of moderate to vigorous activity.

This new recommendation, along with the previous ones pertaining to behavioral interventions for lifestyle changes, make it clear that intensive interventions are needed to achieve meaningful change. Simple advice from a clinician will have little to no effect.

Task Force reviews evidence on HTN, smoking cessation in young people

In 2020 the Task Force completed reviews of evidence relevant to screening for high blood pressure¹¹ and intervening for tobacco prevention and cessation in children and adolescents.¹² The Task Force concluded that the evidence is insufficient to make a judgment on screening for high blood pressure and for providing smoking cessation interventions. It did, however, reaffirm a previous recommendation to provide interventions to children and adolescents to prevent tobacco and e-cigarette use.

Screening for asymptomatic carotid artery stenosis is discouraged due to a lack of evidence for benefit in detection, and on evidence that false-positives lead to harm from procedures such as endarterectomy.

The 2 “I” statements are in disagreement with recommendations of other professional organizations. The American Academy of Pediatrics (AAP) and the American Heart Association recommend routine screening for high blood pressure starting at age 3 years. And the AAP recommends screening teenagers for tobacco use and offering tobacco dependence treatment, referral, or both (including pharmacotherapy) when indicated. E-cigarettes are not recommended as a treatment for tobacco dependence.²⁰

Continue to: The difference between...

The difference between the methods used by the Task Force and other guideline-­producing organizations becomes apparent when it comes to recommendations pertaining to children and adolescents, for whom long-term outcome-oriented studies on prevention issues are rare. The Task Force is unwilling to make recommendations when evidence does not exist. The AAP often makes recommendations based on expert opinion consensus in such situations. One notable part of each Task Force recommendation statement is a discussion of what other organizations recommend on the same topic so that these differences can be openly described.

Better Task Force funding could expand topic coverage

It is worth revisiting 2 issues that were pointed out in last year’s USPSTF summary in this column.¹ First, the Task Force methods are robust and evidence based, and recommendations therefore are rarely changed once they are made at an “A”, “B”, or “D” level. Second, Task Force resources are finite, and thus, the group is currently unable to update previous recommendations with greater frequency or to consider many new topics. In the past 2 years, the Task Force has developed recommendations on only 2 completely new topics. Hopefully, its budget can be expanded so that new topics can be added in the future.

Since the last Practice Alert update on recommendations made by the US Preventive Services Task Force,¹ the Task Force has completed work on 12 topics (TABLE 1).^2-17 Five of these topics have been discussed in JFP audio recordings, and the links are provided in TABLE 1.

This latest Task Force endeavor resulted in 18 recommendations (TABLE 2), all of which reaffirm previous recommendations on these topics and expand the scope of 2. There were 2 “A” recommendations, 6 “B” recommendations, 2 “D” recommendations, and 8 “I” statements, indicating that there was insufficient evidence to assess effectiveness or harms. The willingness to make “I” statements when there is little or no evidence on the intervention being assessed distinguishes the USPSTF from other clinical guideline committees.

Screening for carotid artery stenosis

One of the “D” recommendations this past year reaffirms the prior recommendation against screening for carotid artery stenosis in asymptomatic adults—ie, those without a history of transient ischemic attack, stroke, or neurologic signs or symptoms that might be caused by carotid artery stenosis.² The screening tests the Task Force researched included carotid duplex ultrasonography (DUS), magnetic resonance angiography, and computed tomography angiography. The Task Force did not look at the value of auscultation for carotid bruits because it has been proven to be inaccurate and they do not consider it to be a useful screening tool. 

The Task Force based its “D” recommendation on a lack of evidence for any benefit in detecting asymptomatic carotid artery stenosis, and on evidence that screening can lead to harms through false-positive tests and potential complications from carotid endarterectomy and carotid artery angioplasty and stenting. In its clinical considerations, the Task Force emphasized the primary prevention of atherosclerotic disease by focusing on the following actions:

• screening for high blood pressure in adults
• encouraging tobacco smoking cessation in adults
• promoting a healthy diet and physical activity in adults with cardiovascular risk factors
• recommending aspirin use to prevent cardiovascular disease and colorectal cancer
• advising statin use for the primary prevention of cardiovascular disease in adults ages 45 to 75 years who have 1 or more risk factors (hyperlipidemia, diabetes, hypertension, smoking) and those with a 10-year risk of a cardiovascular event of 10% or greater.

This “D” recommendation differs from recommendations made by other professional organizations, some of which recommend testing with DUS for asymptomatic patients with a carotid bruit, and others that recommend DUS screening in patients with multiple risk factors for stroke and in those with known peripheral artery disease or other cardiovascular disease.^18,19

Smoking cessation in adults

Smoking tobacco is the leading preventable cause of death in the United States, causing about 480,000 deaths annually.³ Smoking during pregnancy increases the risk of complications including miscarriage, congenital anomalies, stillbirth, fetal growth restriction, preterm birth, and placental abruption.

The Task Force published recommendations earlier this year advising all clinicians to ask all adult patients about tobacco use; and, for those who smoke, to provide (or refer them to) smoking cessation behavioral therapy. The Task Force also recommends prescribing pharmacotherapy approved by the Food and Drug Administration (FDA) for smoking cessation for nonpregnant adults. (There is a lack of information to assess the harms and benefits of smoking cessation pharmacotherapy during pregnancy.)

Continue to: FDA-approved medications...

The Task Force recommends prescribing pharmacotherapy approved by the FDA for smoking cessation for nonpregnant adults.

FDA-approved medications for treating tobacco smoking dependence are nicotine replacement therapy (NRT), bupropion hydrochloride, and varenicline.³ NRT is available in transdermal patches, lozenges, gum, inhalers, and nasal sprays.

In addition, the Task Force indicates that there is insufficient evidence to assess the benefits and harms of e-cigarettes when used as a method of achieving smoking cessation: “Few randomized trials have evaluated the effectiveness of e-cigarettes to increase tobacco smoking cessation in nonpregnant adults, and no trials have evaluated e-­cigarettes for tobacco smoking cessation in pregnant persons.”⁴

Hepatitis B infection screening

The Task Force reaffirmed a previous recommendation to screen for hepatitis B virus (HBV) infection only in adults who are at high risk,⁵ rather than universal screening that it recommends for hepatitis C virus infection (HCV).⁷ (See: https://bit.ly/3tt064Q). The Task Force has a separate recommendation to screen all pregnant women for hepatitis B at the first prenatal visit.⁶

Those at high risk for hepatitis B who should be screened include individuals born in countries or regions of the world with a hepatitis B surface antigen (HBsAg) prevalence ≥ 2% and individuals born in the United States who have not received HBV vaccine and whose parents were born in regions with an HBsAg prevalence ≥ 8%.⁵ (A table listing countries with HBsAg ≥ 8%—as well as those in lower prevalence categories—is included with the recommendation.⁵)

Screening individuals at high risk for HBV infection is important because nearly two-thirds of those infected are unaware of their condition.

HBV screening should also be offered to other high-risk groups that have a prevalence of positive HBsAg ≥ 2%: those who have injected drugs in the past or are currently injecting drugs; men who have sex with men; individuals with HIV; and sex partners, needle-sharing contacts, and household contacts of people known to be HBsAg positive.⁵

Continue to: It is estimated that...

It is estimated that > 860,000 people in the United States have chronic HBV infection and that close to two-thirds of them are unaware of their infection.⁵ The screening test for HBV is highly accurate; sensitivity and specificity are both > 98%.⁵ While there is no direct evidence that screening, detecting, and treating asymptomatic HBV infection reduces morbidity and mortality, the Task Force felt that the evidence for improvement in multiple outcomes in those with HBV when treated with antiviral regimens was sufficient to support the recommendation.

Screening for bacterial vaginosis in pregnancy

While bacterial vaginosis (BV) is associated with a two-fold risk of preterm delivery, treating BV during pregnancy does not seem to reduce this risk, indicating that some other variable is involved.⁸ In addition, studies that looked at screening for, and treatment of, ­asymptomatic BV in pregnant women at high risk for preterm delivery (defined primarily as those with a previous preterm delivery) have shown inconsistent results. There is the potential for harm in treating BV in pregnancy, chiefly involving gastrointestinal upset caused by metronidazole or clindamycin.

Given that there are no benefits—and some harms—resulting from treatment, the Task Force recommends against screening for BV in non-high-risk pregnant women. A lack of sufficient information to assess any potential benefits to screening in high-risk pregnancies led the Task Force to an “I” statement on this question.⁸

Behavioral counseling on healthy diet, exercise for adults with CV risks

Cardiovascular disease (CVD) remains the number one cause of death in the United States. The major risk factors for CVD, which can be modified, are high blood pressure, hyperlipidemia, diabetes, smoking, obesity or overweight, and lack of physical activity.

The Task Force has previously recommended intensive behavioral interventions to improve nutrition and physical activity in those who are overweight/obese and in those with abnormal blood glucose levels,⁹ and has addressed smoking prevention and cessation.⁴ This new recommendation applies to those with other CVD risks such as high blood pressure and/or hyperlipidemia and those with an estimated 10-year CVD risk of ≥ 7.5%.¹⁰

Continue to: Behavioral interventions...

Behavioral interventions included in the Task Force analysis employed a median of 12 contacts and an estimated 6 hours of contact time over 6 to 18 months.¹⁰ Most interventions involved motivational interviewing and instruction on behavioral change methods. These interventions can be provided by primary care clinicians, as well as a wide range of other trained professionals. The Affordable Care Act dictates that all “A” and “B” recommendations must be provided by commercial health plans at no out-of-pocket expense for the patient.

Nutritional advice should include reductions in saturated fats, salt, and sugars and increases in fruits, vegetables, and whole grains. The Mediterranean diet and the Dietary Approaches to Stop Hypertension (DASH) diet are often recommended.¹⁰ Physical activity counseling should advocate for 90 to 180 minutes per week of moderate to vigorous activity.

This new recommendation, along with the previous ones pertaining to behavioral interventions for lifestyle changes, make it clear that intensive interventions are needed to achieve meaningful change. Simple advice from a clinician will have little to no effect.

Task Force reviews evidence on HTN, smoking cessation in young people

In 2020 the Task Force completed reviews of evidence relevant to screening for high blood pressure¹¹ and intervening for tobacco prevention and cessation in children and adolescents.¹² The Task Force concluded that the evidence is insufficient to make a judgment on screening for high blood pressure and for providing smoking cessation interventions. It did, however, reaffirm a previous recommendation to provide interventions to children and adolescents to prevent tobacco and e-cigarette use.

Screening for asymptomatic carotid artery stenosis is discouraged due to a lack of evidence for benefit in detection, and on evidence that false-positives lead to harm from procedures such as endarterectomy.

The 2 “I” statements are in disagreement with recommendations of other professional organizations. The American Academy of Pediatrics (AAP) and the American Heart Association recommend routine screening for high blood pressure starting at age 3 years. And the AAP recommends screening teenagers for tobacco use and offering tobacco dependence treatment, referral, or both (including pharmacotherapy) when indicated. E-cigarettes are not recommended as a treatment for tobacco dependence.²⁰

Continue to: The difference between...

The difference between the methods used by the Task Force and other guideline-­producing organizations becomes apparent when it comes to recommendations pertaining to children and adolescents, for whom long-term outcome-oriented studies on prevention issues are rare. The Task Force is unwilling to make recommendations when evidence does not exist. The AAP often makes recommendations based on expert opinion consensus in such situations. One notable part of each Task Force recommendation statement is a discussion of what other organizations recommend on the same topic so that these differences can be openly described.

Better Task Force funding could expand topic coverage

It is worth revisiting 2 issues that were pointed out in last year’s USPSTF summary in this column.¹ First, the Task Force methods are robust and evidence based, and recommendations therefore are rarely changed once they are made at an “A”, “B”, or “D” level. Second, Task Force resources are finite, and thus, the group is currently unable to update previous recommendations with greater frequency or to consider many new topics. In the past 2 years, the Task Force has developed recommendations on only 2 completely new topics. Hopefully, its budget can be expanded so that new topics can be added in the future.

Since the last Practice Alert update on recommendations made by the US Preventive Services Task Force,¹ the Task Force has completed work on 12 topics (TABLE 1).^2-17 Five of these topics have been discussed in JFP audio recordings, and the links are provided in TABLE 1.

This latest Task Force endeavor resulted in 18 recommendations (TABLE 2), all of which reaffirm previous recommendations on these topics and expand the scope of 2. There were 2 “A” recommendations, 6 “B” recommendations, 2 “D” recommendations, and 8 “I” statements, indicating that there was insufficient evidence to assess effectiveness or harms. The willingness to make “I” statements when there is little or no evidence on the intervention being assessed distinguishes the USPSTF from other clinical guideline committees.

Screening for carotid artery stenosis

One of the “D” recommendations this past year reaffirms the prior recommendation against screening for carotid artery stenosis in asymptomatic adults—ie, those without a history of transient ischemic attack, stroke, or neurologic signs or symptoms that might be caused by carotid artery stenosis.² The screening tests the Task Force researched included carotid duplex ultrasonography (DUS), magnetic resonance angiography, and computed tomography angiography. The Task Force did not look at the value of auscultation for carotid bruits because it has been proven to be inaccurate and they do not consider it to be a useful screening tool. 

The Task Force based its “D” recommendation on a lack of evidence for any benefit in detecting asymptomatic carotid artery stenosis, and on evidence that screening can lead to harms through false-positive tests and potential complications from carotid endarterectomy and carotid artery angioplasty and stenting. In its clinical considerations, the Task Force emphasized the primary prevention of atherosclerotic disease by focusing on the following actions:

• screening for high blood pressure in adults
• encouraging tobacco smoking cessation in adults
• promoting a healthy diet and physical activity in adults with cardiovascular risk factors
• recommending aspirin use to prevent cardiovascular disease and colorectal cancer
• advising statin use for the primary prevention of cardiovascular disease in adults ages 45 to 75 years who have 1 or more risk factors (hyperlipidemia, diabetes, hypertension, smoking) and those with a 10-year risk of a cardiovascular event of 10% or greater.

This “D” recommendation differs from recommendations made by other professional organizations, some of which recommend testing with DUS for asymptomatic patients with a carotid bruit, and others that recommend DUS screening in patients with multiple risk factors for stroke and in those with known peripheral artery disease or other cardiovascular disease.^18,19

Smoking cessation in adults

Smoking tobacco is the leading preventable cause of death in the United States, causing about 480,000 deaths annually.³ Smoking during pregnancy increases the risk of complications including miscarriage, congenital anomalies, stillbirth, fetal growth restriction, preterm birth, and placental abruption.

The Task Force published recommendations earlier this year advising all clinicians to ask all adult patients about tobacco use; and, for those who smoke, to provide (or refer them to) smoking cessation behavioral therapy. The Task Force also recommends prescribing pharmacotherapy approved by the Food and Drug Administration (FDA) for smoking cessation for nonpregnant adults. (There is a lack of information to assess the harms and benefits of smoking cessation pharmacotherapy during pregnancy.)

Continue to: FDA-approved medications...

The Task Force recommends prescribing pharmacotherapy approved by the FDA for smoking cessation for nonpregnant adults.

FDA-approved medications for treating tobacco smoking dependence are nicotine replacement therapy (NRT), bupropion hydrochloride, and varenicline.³ NRT is available in transdermal patches, lozenges, gum, inhalers, and nasal sprays.

In addition, the Task Force indicates that there is insufficient evidence to assess the benefits and harms of e-cigarettes when used as a method of achieving smoking cessation: “Few randomized trials have evaluated the effectiveness of e-cigarettes to increase tobacco smoking cessation in nonpregnant adults, and no trials have evaluated e-­cigarettes for tobacco smoking cessation in pregnant persons.”⁴

Hepatitis B infection screening

The Task Force reaffirmed a previous recommendation to screen for hepatitis B virus (HBV) infection only in adults who are at high risk,⁵ rather than universal screening that it recommends for hepatitis C virus infection (HCV).⁷ (See: https://bit.ly/3tt064Q). The Task Force has a separate recommendation to screen all pregnant women for hepatitis B at the first prenatal visit.⁶

Those at high risk for hepatitis B who should be screened include individuals born in countries or regions of the world with a hepatitis B surface antigen (HBsAg) prevalence ≥ 2% and individuals born in the United States who have not received HBV vaccine and whose parents were born in regions with an HBsAg prevalence ≥ 8%.⁵ (A table listing countries with HBsAg ≥ 8%—as well as those in lower prevalence categories—is included with the recommendation.⁵)

Screening individuals at high risk for HBV infection is important because nearly two-thirds of those infected are unaware of their condition.

HBV screening should also be offered to other high-risk groups that have a prevalence of positive HBsAg ≥ 2%: those who have injected drugs in the past or are currently injecting drugs; men who have sex with men; individuals with HIV; and sex partners, needle-sharing contacts, and household contacts of people known to be HBsAg positive.⁵

Continue to: It is estimated that...

It is estimated that > 860,000 people in the United States have chronic HBV infection and that close to two-thirds of them are unaware of their infection.⁵ The screening test for HBV is highly accurate; sensitivity and specificity are both > 98%.⁵ While there is no direct evidence that screening, detecting, and treating asymptomatic HBV infection reduces morbidity and mortality, the Task Force felt that the evidence for improvement in multiple outcomes in those with HBV when treated with antiviral regimens was sufficient to support the recommendation.

Screening for bacterial vaginosis in pregnancy

While bacterial vaginosis (BV) is associated with a two-fold risk of preterm delivery, treating BV during pregnancy does not seem to reduce this risk, indicating that some other variable is involved.⁸ In addition, studies that looked at screening for, and treatment of, ­asymptomatic BV in pregnant women at high risk for preterm delivery (defined primarily as those with a previous preterm delivery) have shown inconsistent results. There is the potential for harm in treating BV in pregnancy, chiefly involving gastrointestinal upset caused by metronidazole or clindamycin.

Given that there are no benefits—and some harms—resulting from treatment, the Task Force recommends against screening for BV in non-high-risk pregnant women. A lack of sufficient information to assess any potential benefits to screening in high-risk pregnancies led the Task Force to an “I” statement on this question.⁸

Behavioral counseling on healthy diet, exercise for adults with CV risks

Cardiovascular disease (CVD) remains the number one cause of death in the United States. The major risk factors for CVD, which can be modified, are high blood pressure, hyperlipidemia, diabetes, smoking, obesity or overweight, and lack of physical activity.

The Task Force has previously recommended intensive behavioral interventions to improve nutrition and physical activity in those who are overweight/obese and in those with abnormal blood glucose levels,⁹ and has addressed smoking prevention and cessation.⁴ This new recommendation applies to those with other CVD risks such as high blood pressure and/or hyperlipidemia and those with an estimated 10-year CVD risk of ≥ 7.5%.¹⁰

Continue to: Behavioral interventions...

Behavioral interventions included in the Task Force analysis employed a median of 12 contacts and an estimated 6 hours of contact time over 6 to 18 months.¹⁰ Most interventions involved motivational interviewing and instruction on behavioral change methods. These interventions can be provided by primary care clinicians, as well as a wide range of other trained professionals. The Affordable Care Act dictates that all “A” and “B” recommendations must be provided by commercial health plans at no out-of-pocket expense for the patient.

Nutritional advice should include reductions in saturated fats, salt, and sugars and increases in fruits, vegetables, and whole grains. The Mediterranean diet and the Dietary Approaches to Stop Hypertension (DASH) diet are often recommended.¹⁰ Physical activity counseling should advocate for 90 to 180 minutes per week of moderate to vigorous activity.

This new recommendation, along with the previous ones pertaining to behavioral interventions for lifestyle changes, make it clear that intensive interventions are needed to achieve meaningful change. Simple advice from a clinician will have little to no effect.

Task Force reviews evidence on HTN, smoking cessation in young people

In 2020 the Task Force completed reviews of evidence relevant to screening for high blood pressure¹¹ and intervening for tobacco prevention and cessation in children and adolescents.¹² The Task Force concluded that the evidence is insufficient to make a judgment on screening for high blood pressure and for providing smoking cessation interventions. It did, however, reaffirm a previous recommendation to provide interventions to children and adolescents to prevent tobacco and e-cigarette use.

Screening for asymptomatic carotid artery stenosis is discouraged due to a lack of evidence for benefit in detection, and on evidence that false-positives lead to harm from procedures such as endarterectomy.

The 2 “I” statements are in disagreement with recommendations of other professional organizations. The American Academy of Pediatrics (AAP) and the American Heart Association recommend routine screening for high blood pressure starting at age 3 years. And the AAP recommends screening teenagers for tobacco use and offering tobacco dependence treatment, referral, or both (including pharmacotherapy) when indicated. E-cigarettes are not recommended as a treatment for tobacco dependence.²⁰

Continue to: The difference between...

The difference between the methods used by the Task Force and other guideline-­producing organizations becomes apparent when it comes to recommendations pertaining to children and adolescents, for whom long-term outcome-oriented studies on prevention issues are rare. The Task Force is unwilling to make recommendations when evidence does not exist. The AAP often makes recommendations based on expert opinion consensus in such situations. One notable part of each Task Force recommendation statement is a discussion of what other organizations recommend on the same topic so that these differences can be openly described.

Better Task Force funding could expand topic coverage

It is worth revisiting 2 issues that were pointed out in last year’s USPSTF summary in this column.¹ First, the Task Force methods are robust and evidence based, and recommendations therefore are rarely changed once they are made at an “A”, “B”, or “D” level. Second, Task Force resources are finite, and thus, the group is currently unable to update previous recommendations with greater frequency or to consider many new topics. In the past 2 years, the Task Force has developed recommendations on only 2 completely new topics. Hopefully, its budget can be expanded so that new topics can be added in the future.

Changing the continuous antibiotic prophylactic agent had no significant effect on the risk of a second infection in children with breakthrough urinary tract infections (UTIs), based on data from 62 children treated at a single center.

Continuous antibiotic prophylaxis (CAP) is often used for UTI prevention in children with febrile UTIs or anomalies that predispose them to UTIs, such as vesicoureteral reflux (VUR) or bladder and bowel dysfunction, said Lane M. Shish, MPH, of the University of Washington, Bothell, and colleagues in a poster (#1245) presented at the Pediatric Academic Societies annual meeting.

CAP, once initiated, is used until a planned endpoint or a breakthrough UTI, at which point alternative treatments usually include surgical intervention or a CAP agent change, the researchers said. However, changing the CAP agent is based on consensus without evidence of benefit, they noted.

To evaluate the potential effect of switching or maintaining CAP in cases of breakthrough UTIs, the researchers conducted a retrospective cohort study of all patients younger than 18 years on CAP for UTI prevention enrolled in a pediatric urology registry between January 2013 and August 2020.

All patients experienced a breakthrough UTI while on CAP; CAP was changed for 24 patients and left unchanged for 38 patients.

The primary outcome of second-breakthrough infections occurred in 12 of the changed CAP group and 22 of the unchanged group, with a relative risk of 0.86. The percentage of second breakthrough UTIs resistant to the current CAP was not significantly different between the changed and unchanged CAP groups (75% vs. 77%; P = 0.88).

The researchers also identified a rate ratio of 0.67 for a second breakthrough UTI in the changed CAP group, and found that approximately one-third of these patients (33.3%) developed antibiotic resistance to their initial antibiotic agent and the changed antibiotic agent.

The study findings were limited by several factors, including the retrospective design and small sample size, the researchers noted.

However, the results suggest that changing the CAP after an initial breakthrough UTI in children did not increase the risk of a second breakthrough UTI, and that CAP changing did introduce a risk of developing a second UTI with increased CAP resistance, the researchers noted. The results support leaving a child’s CAP unchanged after an initial breakthrough UTI, although additional research is needed to verify the findings, including studies involving a larger cohort with a multi-institutional prospective evaluation, they concluded.

Manage UTIs to reduce recurrence and resistance

“As we know, avoiding recurrent UTIs is important in preserving renal function in pediatric patients,” said Tim Joos, MD, a Seattle-based clinician with a combination internal medicine/pediatrics practice, in an interview.

“Avoiding recurrent UTIs is also important to avoid the development and spread of multidrug-resistant organisms,” he said.

Dr. Joos said he was surprised by some of the study findings. “I was surprised that, over the course of this 7-year retrospective review, overall only approximately 50% of patients with a first breakthrough UTI on CAP developed a second breakthrough UTI,” he noted. “Also, the relative risk of a second UTI was not significantly affected by whether the CAP antibiotic was changed after the first infection,” he said. “It would be interesting to see whether these results hold up in a randomized, prospective study,” he added.

The study received no outside funding. The researchers had no financial conflicts to disclose. Dr. Joos had no financial conflicts to disclose, but serves as a member of the Pediatric News Editorial Advisory Board.

Changing the continuous antibiotic prophylactic agent had no significant effect on the risk of a second infection in children with breakthrough urinary tract infections (UTIs), based on data from 62 children treated at a single center.

Continuous antibiotic prophylaxis (CAP) is often used for UTI prevention in children with febrile UTIs or anomalies that predispose them to UTIs, such as vesicoureteral reflux (VUR) or bladder and bowel dysfunction, said Lane M. Shish, MPH, of the University of Washington, Bothell, and colleagues in a poster (#1245) presented at the Pediatric Academic Societies annual meeting.

CAP, once initiated, is used until a planned endpoint or a breakthrough UTI, at which point alternative treatments usually include surgical intervention or a CAP agent change, the researchers said. However, changing the CAP agent is based on consensus without evidence of benefit, they noted.

To evaluate the potential effect of switching or maintaining CAP in cases of breakthrough UTIs, the researchers conducted a retrospective cohort study of all patients younger than 18 years on CAP for UTI prevention enrolled in a pediatric urology registry between January 2013 and August 2020.

All patients experienced a breakthrough UTI while on CAP; CAP was changed for 24 patients and left unchanged for 38 patients.

The primary outcome of second-breakthrough infections occurred in 12 of the changed CAP group and 22 of the unchanged group, with a relative risk of 0.86. The percentage of second breakthrough UTIs resistant to the current CAP was not significantly different between the changed and unchanged CAP groups (75% vs. 77%; P = 0.88).

The researchers also identified a rate ratio of 0.67 for a second breakthrough UTI in the changed CAP group, and found that approximately one-third of these patients (33.3%) developed antibiotic resistance to their initial antibiotic agent and the changed antibiotic agent.

The study findings were limited by several factors, including the retrospective design and small sample size, the researchers noted.

However, the results suggest that changing the CAP after an initial breakthrough UTI in children did not increase the risk of a second breakthrough UTI, and that CAP changing did introduce a risk of developing a second UTI with increased CAP resistance, the researchers noted. The results support leaving a child’s CAP unchanged after an initial breakthrough UTI, although additional research is needed to verify the findings, including studies involving a larger cohort with a multi-institutional prospective evaluation, they concluded.

Manage UTIs to reduce recurrence and resistance

“As we know, avoiding recurrent UTIs is important in preserving renal function in pediatric patients,” said Tim Joos, MD, a Seattle-based clinician with a combination internal medicine/pediatrics practice, in an interview.

“Avoiding recurrent UTIs is also important to avoid the development and spread of multidrug-resistant organisms,” he said.

Dr. Joos said he was surprised by some of the study findings. “I was surprised that, over the course of this 7-year retrospective review, overall only approximately 50% of patients with a first breakthrough UTI on CAP developed a second breakthrough UTI,” he noted. “Also, the relative risk of a second UTI was not significantly affected by whether the CAP antibiotic was changed after the first infection,” he said. “It would be interesting to see whether these results hold up in a randomized, prospective study,” he added.

The study received no outside funding. The researchers had no financial conflicts to disclose. Dr. Joos had no financial conflicts to disclose, but serves as a member of the Pediatric News Editorial Advisory Board.

Changing the continuous antibiotic prophylactic agent had no significant effect on the risk of a second infection in children with breakthrough urinary tract infections (UTIs), based on data from 62 children treated at a single center.

Continuous antibiotic prophylaxis (CAP) is often used for UTI prevention in children with febrile UTIs or anomalies that predispose them to UTIs, such as vesicoureteral reflux (VUR) or bladder and bowel dysfunction, said Lane M. Shish, MPH, of the University of Washington, Bothell, and colleagues in a poster (#1245) presented at the Pediatric Academic Societies annual meeting.

CAP, once initiated, is used until a planned endpoint or a breakthrough UTI, at which point alternative treatments usually include surgical intervention or a CAP agent change, the researchers said. However, changing the CAP agent is based on consensus without evidence of benefit, they noted.

To evaluate the potential effect of switching or maintaining CAP in cases of breakthrough UTIs, the researchers conducted a retrospective cohort study of all patients younger than 18 years on CAP for UTI prevention enrolled in a pediatric urology registry between January 2013 and August 2020.

All patients experienced a breakthrough UTI while on CAP; CAP was changed for 24 patients and left unchanged for 38 patients.

The primary outcome of second-breakthrough infections occurred in 12 of the changed CAP group and 22 of the unchanged group, with a relative risk of 0.86. The percentage of second breakthrough UTIs resistant to the current CAP was not significantly different between the changed and unchanged CAP groups (75% vs. 77%; P = 0.88).

The researchers also identified a rate ratio of 0.67 for a second breakthrough UTI in the changed CAP group, and found that approximately one-third of these patients (33.3%) developed antibiotic resistance to their initial antibiotic agent and the changed antibiotic agent.

The study findings were limited by several factors, including the retrospective design and small sample size, the researchers noted.

However, the results suggest that changing the CAP after an initial breakthrough UTI in children did not increase the risk of a second breakthrough UTI, and that CAP changing did introduce a risk of developing a second UTI with increased CAP resistance, the researchers noted. The results support leaving a child’s CAP unchanged after an initial breakthrough UTI, although additional research is needed to verify the findings, including studies involving a larger cohort with a multi-institutional prospective evaluation, they concluded.

Manage UTIs to reduce recurrence and resistance

“As we know, avoiding recurrent UTIs is important in preserving renal function in pediatric patients,” said Tim Joos, MD, a Seattle-based clinician with a combination internal medicine/pediatrics practice, in an interview.

“Avoiding recurrent UTIs is also important to avoid the development and spread of multidrug-resistant organisms,” he said.

Dr. Joos said he was surprised by some of the study findings. “I was surprised that, over the course of this 7-year retrospective review, overall only approximately 50% of patients with a first breakthrough UTI on CAP developed a second breakthrough UTI,” he noted. “Also, the relative risk of a second UTI was not significantly affected by whether the CAP antibiotic was changed after the first infection,” he said. “It would be interesting to see whether these results hold up in a randomized, prospective study,” he added.

The study received no outside funding. The researchers had no financial conflicts to disclose. Dr. Joos had no financial conflicts to disclose, but serves as a member of the Pediatric News Editorial Advisory Board.

Finerenone, an investigational agent from a new drug class, just scored a second pivotal trial win after showing significant benefit for slowing progression of diabetic kidney disease in patients with type 2 diabetes in the FIDELIO-DKD pivotal trial with more than 5,700 patients.

Top-line results from FIGARO-DKD showed significant benefit for the primary endpoint of cardiovascular death and nonfatal cardiovascular disease endpoints in a placebo-controlled trial with about 7,400 patients with type 2 diabetes, reported Bayer, the company developing finerenone in statement released on May 10, 2021.

Based on the FIDELIO-DKD results, finerenone is currently under review by the U.S. Food and Drug Administration for marketing approval as a treatment for patients with type 2 diabetes and chronic kidney disease. FIDELIO-DKD, in addition to the primary endpoint that focused on slowing progression of diabetic kidney disease, had a secondary endpoint that assessed the combined incidence on treatment of cardiovascular death, or nonfatal episodes of stroke, MI, or hospitalization for heart failure. Results from the study published in 2020 in the New England Journal of Medicine showed that finerenone was safe and effective for both endpoints.

In the current study, FIGARO-DKD, run at more than 1,000 sites in 47 countries, these endpoints flipped. The primary outcome was a composite of cardiovascular death or nonfatal cardiovascular disease events, and the secondary outcome was prevention of DKD progression.

Other than stating the results significantly fulfilled FIGARO-DKD’s primary endpoint of reducing the incidence of combined cardiovascular disease endpoints, the release gave no further outcome details. The release noted that the enrolled patient cohort in FIGARO-DKD included more patients with earlier-stage chronic kidney disease, compared with FIDELIO-DKD.

Finerenone is a first-in-class investigational nonsteroidal, selective mineralocorticoid receptor antagonist (MRA). As an MRA it shares certain activities with the steroidal MRAs spironolactone and eplerenone. But the absence of a steroidal structure means that finerenone does not cause steroidal adverse effects such as gynecomastia. Results in FIDELIO-DKD showed that finerenone caused more hyperkalemia than placebo, but the level of hyperkalemia that it causes relative to spironolactone or eplerenone remains uncertain.

[email protected]

Finerenone, an investigational agent from a new drug class, just scored a second pivotal trial win after showing significant benefit for slowing progression of diabetic kidney disease in patients with type 2 diabetes in the FIDELIO-DKD pivotal trial with more than 5,700 patients.

Top-line results from FIGARO-DKD showed significant benefit for the primary endpoint of cardiovascular death and nonfatal cardiovascular disease endpoints in a placebo-controlled trial with about 7,400 patients with type 2 diabetes, reported Bayer, the company developing finerenone in statement released on May 10, 2021.

Based on the FIDELIO-DKD results, finerenone is currently under review by the U.S. Food and Drug Administration for marketing approval as a treatment for patients with type 2 diabetes and chronic kidney disease. FIDELIO-DKD, in addition to the primary endpoint that focused on slowing progression of diabetic kidney disease, had a secondary endpoint that assessed the combined incidence on treatment of cardiovascular death, or nonfatal episodes of stroke, MI, or hospitalization for heart failure. Results from the study published in 2020 in the New England Journal of Medicine showed that finerenone was safe and effective for both endpoints.

In the current study, FIGARO-DKD, run at more than 1,000 sites in 47 countries, these endpoints flipped. The primary outcome was a composite of cardiovascular death or nonfatal cardiovascular disease events, and the secondary outcome was prevention of DKD progression.

Other than stating the results significantly fulfilled FIGARO-DKD’s primary endpoint of reducing the incidence of combined cardiovascular disease endpoints, the release gave no further outcome details. The release noted that the enrolled patient cohort in FIGARO-DKD included more patients with earlier-stage chronic kidney disease, compared with FIDELIO-DKD.

Finerenone is a first-in-class investigational nonsteroidal, selective mineralocorticoid receptor antagonist (MRA). As an MRA it shares certain activities with the steroidal MRAs spironolactone and eplerenone. But the absence of a steroidal structure means that finerenone does not cause steroidal adverse effects such as gynecomastia. Results in FIDELIO-DKD showed that finerenone caused more hyperkalemia than placebo, but the level of hyperkalemia that it causes relative to spironolactone or eplerenone remains uncertain.

[email protected]

Finerenone, an investigational agent from a new drug class, just scored a second pivotal trial win after showing significant benefit for slowing progression of diabetic kidney disease in patients with type 2 diabetes in the FIDELIO-DKD pivotal trial with more than 5,700 patients.

Top-line results from FIGARO-DKD showed significant benefit for the primary endpoint of cardiovascular death and nonfatal cardiovascular disease endpoints in a placebo-controlled trial with about 7,400 patients with type 2 diabetes, reported Bayer, the company developing finerenone in statement released on May 10, 2021.

Based on the FIDELIO-DKD results, finerenone is currently under review by the U.S. Food and Drug Administration for marketing approval as a treatment for patients with type 2 diabetes and chronic kidney disease. FIDELIO-DKD, in addition to the primary endpoint that focused on slowing progression of diabetic kidney disease, had a secondary endpoint that assessed the combined incidence on treatment of cardiovascular death, or nonfatal episodes of stroke, MI, or hospitalization for heart failure. Results from the study published in 2020 in the New England Journal of Medicine showed that finerenone was safe and effective for both endpoints.

In the current study, FIGARO-DKD, run at more than 1,000 sites in 47 countries, these endpoints flipped. The primary outcome was a composite of cardiovascular death or nonfatal cardiovascular disease events, and the secondary outcome was prevention of DKD progression.

Other than stating the results significantly fulfilled FIGARO-DKD’s primary endpoint of reducing the incidence of combined cardiovascular disease endpoints, the release gave no further outcome details. The release noted that the enrolled patient cohort in FIGARO-DKD included more patients with earlier-stage chronic kidney disease, compared with FIDELIO-DKD.

Finerenone is a first-in-class investigational nonsteroidal, selective mineralocorticoid receptor antagonist (MRA). As an MRA it shares certain activities with the steroidal MRAs spironolactone and eplerenone. But the absence of a steroidal structure means that finerenone does not cause steroidal adverse effects such as gynecomastia. Results in FIDELIO-DKD showed that finerenone caused more hyperkalemia than placebo, but the level of hyperkalemia that it causes relative to spironolactone or eplerenone remains uncertain.

[email protected]

The Food and Drug Administration has approved dapagliflozin (Farxiga, AstraZeneca) to reduce the risk for kidney function decline, kidney failure, cardiovascular death, and hospitalization for heart failure in adult patients with chronic kidney disease (CKD) at risk for disease progression.

“Chronic kidney disease is an important public health issue, and there is a significant unmet need for therapies that slow disease progression and improve outcomes,” said Aliza Thompson, MD, deputy director of the division of cardiology and nephrology at the FDA’s Center for Drug Evaluation and Research. “Today’s approval of Farxiga for the treatment of chronic kidney disease is an important step forward in helping people living with kidney disease.”

Dapagliflozin was approved in 2014 to improve glycemic control in patients with diabetes mellitus, and approval was expanded in 2020 to include treatment of patients with heart failure and reduced ejection fraction, based on results of the DAPA-HF trial.

This new approval in chronic kidney disease was based on results of the DAPA-CKD trial that was stopped early in March 2020 because of efficacy of the treatment.

DAPA-CKD randomly assigned 4,304 patients with CKD but without diabetes to receive either dapagliflozin or placebo. The full study results, reported at the 2020 annual congress of the European Society of Cardiology and simultaneously published in the New England Journal of Medicine, showed that, during a median of 2.4 years, treatment with dapagliflozin led to a significant 31% relative reduction, compared with placebo in the study’s primary outcome, a composite that included at least a 50% drop in estimated glomerular filtration rate, compared with baseline, end-stage kidney disease, kidney transplant, renal death, or cardiovascular death.

Dapagliflozin treatment also cut all-cause mortality by a statistically significant relative reduction of 31%, and another secondary-endpoint analysis showed a statistically significant 29% relative reduction in the rate of cardiovascular death or heart failure hospitalization.

“Farxiga was not studied, nor is expected to be effective, in treating chronic kidney disease among patients with autosomal dominant or recessive polycystic (characterized by multiple cysts) kidney disease or among patients who require or have recently used immunosuppressive therapy to treat kidney disease,” the FDA statement noted.

Dapagliflozin should not be used by patients with a history of serious hypersensitivity reactions to this medication, or who are on dialysis, the agency added. “Serious, life-threatening cases of Fournier’s Gangrene have occurred in patients with diabetes taking Farxiga.”

Patients should consider taking a lower dose of insulin or insulin secretagogue to reduce hypoglycemic risk if they are also taking dapagliflozin. Treatment can also cause dehydration, serious urinary tract infections, genital yeast infections, and metabolic acidosis, the announcement said. “Patients should be assessed for their volume status and kidney function before starting Farxiga.”

Dapagliflozin previously received Fast Track, Breakthrough Therapy, and Priority Review designations for this new indication.

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

The Food and Drug Administration has approved dapagliflozin (Farxiga, AstraZeneca) to reduce the risk for kidney function decline, kidney failure, cardiovascular death, and hospitalization for heart failure in adult patients with chronic kidney disease (CKD) at risk for disease progression.

“Chronic kidney disease is an important public health issue, and there is a significant unmet need for therapies that slow disease progression and improve outcomes,” said Aliza Thompson, MD, deputy director of the division of cardiology and nephrology at the FDA’s Center for Drug Evaluation and Research. “Today’s approval of Farxiga for the treatment of chronic kidney disease is an important step forward in helping people living with kidney disease.”

Dapagliflozin was approved in 2014 to improve glycemic control in patients with diabetes mellitus, and approval was expanded in 2020 to include treatment of patients with heart failure and reduced ejection fraction, based on results of the DAPA-HF trial.

This new approval in chronic kidney disease was based on results of the DAPA-CKD trial that was stopped early in March 2020 because of efficacy of the treatment.

DAPA-CKD randomly assigned 4,304 patients with CKD but without diabetes to receive either dapagliflozin or placebo. The full study results, reported at the 2020 annual congress of the European Society of Cardiology and simultaneously published in the New England Journal of Medicine, showed that, during a median of 2.4 years, treatment with dapagliflozin led to a significant 31% relative reduction, compared with placebo in the study’s primary outcome, a composite that included at least a 50% drop in estimated glomerular filtration rate, compared with baseline, end-stage kidney disease, kidney transplant, renal death, or cardiovascular death.

Dapagliflozin treatment also cut all-cause mortality by a statistically significant relative reduction of 31%, and another secondary-endpoint analysis showed a statistically significant 29% relative reduction in the rate of cardiovascular death or heart failure hospitalization.

“Farxiga was not studied, nor is expected to be effective, in treating chronic kidney disease among patients with autosomal dominant or recessive polycystic (characterized by multiple cysts) kidney disease or among patients who require or have recently used immunosuppressive therapy to treat kidney disease,” the FDA statement noted.

Dapagliflozin should not be used by patients with a history of serious hypersensitivity reactions to this medication, or who are on dialysis, the agency added. “Serious, life-threatening cases of Fournier’s Gangrene have occurred in patients with diabetes taking Farxiga.”

Patients should consider taking a lower dose of insulin or insulin secretagogue to reduce hypoglycemic risk if they are also taking dapagliflozin. Treatment can also cause dehydration, serious urinary tract infections, genital yeast infections, and metabolic acidosis, the announcement said. “Patients should be assessed for their volume status and kidney function before starting Farxiga.”

Dapagliflozin previously received Fast Track, Breakthrough Therapy, and Priority Review designations for this new indication.

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

The Food and Drug Administration has approved dapagliflozin (Farxiga, AstraZeneca) to reduce the risk for kidney function decline, kidney failure, cardiovascular death, and hospitalization for heart failure in adult patients with chronic kidney disease (CKD) at risk for disease progression.

“Chronic kidney disease is an important public health issue, and there is a significant unmet need for therapies that slow disease progression and improve outcomes,” said Aliza Thompson, MD, deputy director of the division of cardiology and nephrology at the FDA’s Center for Drug Evaluation and Research. “Today’s approval of Farxiga for the treatment of chronic kidney disease is an important step forward in helping people living with kidney disease.”

Dapagliflozin was approved in 2014 to improve glycemic control in patients with diabetes mellitus, and approval was expanded in 2020 to include treatment of patients with heart failure and reduced ejection fraction, based on results of the DAPA-HF trial.

This new approval in chronic kidney disease was based on results of the DAPA-CKD trial that was stopped early in March 2020 because of efficacy of the treatment.

DAPA-CKD randomly assigned 4,304 patients with CKD but without diabetes to receive either dapagliflozin or placebo. The full study results, reported at the 2020 annual congress of the European Society of Cardiology and simultaneously published in the New England Journal of Medicine, showed that, during a median of 2.4 years, treatment with dapagliflozin led to a significant 31% relative reduction, compared with placebo in the study’s primary outcome, a composite that included at least a 50% drop in estimated glomerular filtration rate, compared with baseline, end-stage kidney disease, kidney transplant, renal death, or cardiovascular death.

Dapagliflozin treatment also cut all-cause mortality by a statistically significant relative reduction of 31%, and another secondary-endpoint analysis showed a statistically significant 29% relative reduction in the rate of cardiovascular death or heart failure hospitalization.

“Farxiga was not studied, nor is expected to be effective, in treating chronic kidney disease among patients with autosomal dominant or recessive polycystic (characterized by multiple cysts) kidney disease or among patients who require or have recently used immunosuppressive therapy to treat kidney disease,” the FDA statement noted.

Dapagliflozin should not be used by patients with a history of serious hypersensitivity reactions to this medication, or who are on dialysis, the agency added. “Serious, life-threatening cases of Fournier’s Gangrene have occurred in patients with diabetes taking Farxiga.”

Patients should consider taking a lower dose of insulin or insulin secretagogue to reduce hypoglycemic risk if they are also taking dapagliflozin. Treatment can also cause dehydration, serious urinary tract infections, genital yeast infections, and metabolic acidosis, the announcement said. “Patients should be assessed for their volume status and kidney function before starting Farxiga.”

Dapagliflozin previously received Fast Track, Breakthrough Therapy, and Priority Review designations for this new indication.

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