Clinician Reviews

A man in England who was infected with an early strain of COVID-19 was finally cleared 411 days after first testing positive, according to experts in the United Kingdom. 

The man was treated with a mixture of neutralizing monoclonal antibodies, King’s College London said in a news release.

The man, 59, tested positive in December 2020 and tested negative in January 2022. He had a weakened immune system because of a previous kidney transplant. He received three doses of vaccine and his symptoms lessened, but he kept testing positive for COVID.

To find out if the man had a persistent infection or had been infected several times, doctors did a genetic analysis of the virus.

“This revealed that the patient’s infection was a persistent infection with an early COVID variant – a variation of the original Wuhan variant that was dominant in the United Kingdom in the later months of 2020. Analysis found the patient’s virus had multiple mutations since he was first infected,” King’s College said.

The doctors treated him with a Regeneron treatment that is no longer widely used because it’s not effective against newer COVID variants.

“Some new variants of the virus are resistant to all the antibody treatments available in the United Kingdom and Europe. Some people with weakened immune systems are still at risk of severe illness and becoming persistently infected. We are still working to understand the best way to protect and treat them,” Luke Snell, MD, from the King’s College School of Immunology & Microbial Sciences, said in the news release.

This is one of the longest known cases of COVID infection. Another man in England was infected with COVID for 505 days before his death, which King’s College said was the longest known COVID infection.

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

A man in England who was infected with an early strain of COVID-19 was finally cleared 411 days after first testing positive, according to experts in the United Kingdom. 

The man was treated with a mixture of neutralizing monoclonal antibodies, King’s College London said in a news release.

The man, 59, tested positive in December 2020 and tested negative in January 2022. He had a weakened immune system because of a previous kidney transplant. He received three doses of vaccine and his symptoms lessened, but he kept testing positive for COVID.

To find out if the man had a persistent infection or had been infected several times, doctors did a genetic analysis of the virus.

“This revealed that the patient’s infection was a persistent infection with an early COVID variant – a variation of the original Wuhan variant that was dominant in the United Kingdom in the later months of 2020. Analysis found the patient’s virus had multiple mutations since he was first infected,” King’s College said.

The doctors treated him with a Regeneron treatment that is no longer widely used because it’s not effective against newer COVID variants.

“Some new variants of the virus are resistant to all the antibody treatments available in the United Kingdom and Europe. Some people with weakened immune systems are still at risk of severe illness and becoming persistently infected. We are still working to understand the best way to protect and treat them,” Luke Snell, MD, from the King’s College School of Immunology & Microbial Sciences, said in the news release.

This is one of the longest known cases of COVID infection. Another man in England was infected with COVID for 505 days before his death, which King’s College said was the longest known COVID infection.

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

A man in England who was infected with an early strain of COVID-19 was finally cleared 411 days after first testing positive, according to experts in the United Kingdom. 

The man was treated with a mixture of neutralizing monoclonal antibodies, King’s College London said in a news release.

The man, 59, tested positive in December 2020 and tested negative in January 2022. He had a weakened immune system because of a previous kidney transplant. He received three doses of vaccine and his symptoms lessened, but he kept testing positive for COVID.

To find out if the man had a persistent infection or had been infected several times, doctors did a genetic analysis of the virus.

“This revealed that the patient’s infection was a persistent infection with an early COVID variant – a variation of the original Wuhan variant that was dominant in the United Kingdom in the later months of 2020. Analysis found the patient’s virus had multiple mutations since he was first infected,” King’s College said.

The doctors treated him with a Regeneron treatment that is no longer widely used because it’s not effective against newer COVID variants.

“Some new variants of the virus are resistant to all the antibody treatments available in the United Kingdom and Europe. Some people with weakened immune systems are still at risk of severe illness and becoming persistently infected. We are still working to understand the best way to protect and treat them,” Luke Snell, MD, from the King’s College School of Immunology & Microbial Sciences, said in the news release.

This is one of the longest known cases of COVID infection. Another man in England was infected with COVID for 505 days before his death, which King’s College said was the longest known COVID infection.

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

The COVID-19 bivalent Pfizer/BioNTech vaccine triggers a stronger immune response than a fourth dose of the original vaccine, the company reported on Nov. 4, supporting calls by public health officials for eligible people to get this booster before a potential COVID-19 surge this winter.

The company’s ongoing phase 2/3 study of their Omicron BA.4 and BA.5 bivalent – which targets both the virus’ original strain and the two subvariants – shows that the vaccine offered the strongest protection in people older than 55 years.

One month after receiving a 30-mcg booster with the bivalent vaccine, those older than 55 had four times more neutralizing antibodies against these Omicron subvariants, compared with people who received the original monovalent vaccine as a booster in the study.

Researchers compared the geometric mean titer (GMT) levels of these antibodies in three groups before and 1 month after boosting. The 36 people older than 55 years in the released study findings had an GMT level of 896 with the bivalent booster, a level 13 times higher than before this immunization.

For the 38 adults ages 18-55 in the study, the GMT level increased to 606 at 1 month after the bivalent booster, an increase of almost 10-fold, compared with baseline. In a comparator group of 40 people receiving the original vaccine as a fourth dose, the GMT level was 236, or threefold higher than before their booster shot.

The newly released data is “very encouraging and consistent now with three studies all showing a substantial 3-4 fold increased level of neutralizing antibodies versus BA.5 as compared with the original booster,” said Eric Topol, MD, director of the Scripps Research Translational Institute in La Jolla, Calif., and editor-in-chief of Medscape Medical News.

Pfizer and BioNTech announced the updated findings in a Nov. 4 press release.

A booster dose of the BA.4/BA.5-adapted bivalent vaccine is authorized for emergency use by the Food and Drug Administration for ages 5 years and older. The safety and tolerability profile of the Pfizer/BioNTech bivalent booster remains favorable and similar to the original COVID-19 vaccine, the company reported.

Until recently, the BA.5 Omicron variant was the dominant strain in the United States, but is now getting elbowed out by the subvariants BQ.1.1, BQ.1, and BA.4.6, which together make up almost 45% of the circulating virus.
 

Some skepticism

“It is important to note that these data are press-release level, which does not allow a view of the data totality,” Hana El Sahly, MD, professor of molecular virology and microbiology, Baylor College of Medicine, Houston, said in an interview.

“For example, there may be significant differences between the groups, and the release mentions at least one difference that is of importance: the interval since the last vaccination which often affects the response to subsequent boosting,” she said.

Dr. El Sahly added that the findings are not surprising. “In the short term, a variant-specific vaccine produces a higher level of antibody against the variant in the vaccine than the vaccines based on the ancestral strains.”

More researcher results are warranted. “These data do not indicate that these differences between the two vaccines translate into a meaningful clinical benefit at a population level,” Dr. El Sahly said.
 

An uncertain winter ahead

“As we head into the holiday season, we hope these updated data will encourage people to seek out a COVID-19 bivalent booster as soon as they are eligible in order to maintain high levels of protection against the widely circulating Omicron BA.4 and BA.5 sublineages,” Albert Bourla, Pfizer chairman and CEO, stated in the release.

The updated data from the Pfizer/BioNTech study are “all the more reason to get a booster, with added protection also versus BQ.1.1, which will soon become dominant in the U.S.,” Dr. Topol predicted.

It is unclear when the next surge will happen, as COVID-19 does not always follow a seasonal pattern, at least not yet, Dr. El Sahly said. “Regardless, it is reasonable to recommend additional vaccine doses to immunocompromised and frail or older persons. More importantly, influenza vaccination and being up to date on pneumococcal vaccines are highly recommended as soon as feasible, given the early and intense flu season.”

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

The COVID-19 bivalent Pfizer/BioNTech vaccine triggers a stronger immune response than a fourth dose of the original vaccine, the company reported on Nov. 4, supporting calls by public health officials for eligible people to get this booster before a potential COVID-19 surge this winter.

The company’s ongoing phase 2/3 study of their Omicron BA.4 and BA.5 bivalent – which targets both the virus’ original strain and the two subvariants – shows that the vaccine offered the strongest protection in people older than 55 years.

One month after receiving a 30-mcg booster with the bivalent vaccine, those older than 55 had four times more neutralizing antibodies against these Omicron subvariants, compared with people who received the original monovalent vaccine as a booster in the study.

Researchers compared the geometric mean titer (GMT) levels of these antibodies in three groups before and 1 month after boosting. The 36 people older than 55 years in the released study findings had an GMT level of 896 with the bivalent booster, a level 13 times higher than before this immunization.

For the 38 adults ages 18-55 in the study, the GMT level increased to 606 at 1 month after the bivalent booster, an increase of almost 10-fold, compared with baseline. In a comparator group of 40 people receiving the original vaccine as a fourth dose, the GMT level was 236, or threefold higher than before their booster shot.

The newly released data is “very encouraging and consistent now with three studies all showing a substantial 3-4 fold increased level of neutralizing antibodies versus BA.5 as compared with the original booster,” said Eric Topol, MD, director of the Scripps Research Translational Institute in La Jolla, Calif., and editor-in-chief of Medscape Medical News.

Pfizer and BioNTech announced the updated findings in a Nov. 4 press release.

A booster dose of the BA.4/BA.5-adapted bivalent vaccine is authorized for emergency use by the Food and Drug Administration for ages 5 years and older. The safety and tolerability profile of the Pfizer/BioNTech bivalent booster remains favorable and similar to the original COVID-19 vaccine, the company reported.

Until recently, the BA.5 Omicron variant was the dominant strain in the United States, but is now getting elbowed out by the subvariants BQ.1.1, BQ.1, and BA.4.6, which together make up almost 45% of the circulating virus.
 

Some skepticism

“It is important to note that these data are press-release level, which does not allow a view of the data totality,” Hana El Sahly, MD, professor of molecular virology and microbiology, Baylor College of Medicine, Houston, said in an interview.

“For example, there may be significant differences between the groups, and the release mentions at least one difference that is of importance: the interval since the last vaccination which often affects the response to subsequent boosting,” she said.

Dr. El Sahly added that the findings are not surprising. “In the short term, a variant-specific vaccine produces a higher level of antibody against the variant in the vaccine than the vaccines based on the ancestral strains.”

More researcher results are warranted. “These data do not indicate that these differences between the two vaccines translate into a meaningful clinical benefit at a population level,” Dr. El Sahly said.
 

An uncertain winter ahead

“As we head into the holiday season, we hope these updated data will encourage people to seek out a COVID-19 bivalent booster as soon as they are eligible in order to maintain high levels of protection against the widely circulating Omicron BA.4 and BA.5 sublineages,” Albert Bourla, Pfizer chairman and CEO, stated in the release.

The updated data from the Pfizer/BioNTech study are “all the more reason to get a booster, with added protection also versus BQ.1.1, which will soon become dominant in the U.S.,” Dr. Topol predicted.

It is unclear when the next surge will happen, as COVID-19 does not always follow a seasonal pattern, at least not yet, Dr. El Sahly said. “Regardless, it is reasonable to recommend additional vaccine doses to immunocompromised and frail or older persons. More importantly, influenza vaccination and being up to date on pneumococcal vaccines are highly recommended as soon as feasible, given the early and intense flu season.”

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

The COVID-19 bivalent Pfizer/BioNTech vaccine triggers a stronger immune response than a fourth dose of the original vaccine, the company reported on Nov. 4, supporting calls by public health officials for eligible people to get this booster before a potential COVID-19 surge this winter.

The company’s ongoing phase 2/3 study of their Omicron BA.4 and BA.5 bivalent – which targets both the virus’ original strain and the two subvariants – shows that the vaccine offered the strongest protection in people older than 55 years.

One month after receiving a 30-mcg booster with the bivalent vaccine, those older than 55 had four times more neutralizing antibodies against these Omicron subvariants, compared with people who received the original monovalent vaccine as a booster in the study.

Researchers compared the geometric mean titer (GMT) levels of these antibodies in three groups before and 1 month after boosting. The 36 people older than 55 years in the released study findings had an GMT level of 896 with the bivalent booster, a level 13 times higher than before this immunization.

For the 38 adults ages 18-55 in the study, the GMT level increased to 606 at 1 month after the bivalent booster, an increase of almost 10-fold, compared with baseline. In a comparator group of 40 people receiving the original vaccine as a fourth dose, the GMT level was 236, or threefold higher than before their booster shot.

The newly released data is “very encouraging and consistent now with three studies all showing a substantial 3-4 fold increased level of neutralizing antibodies versus BA.5 as compared with the original booster,” said Eric Topol, MD, director of the Scripps Research Translational Institute in La Jolla, Calif., and editor-in-chief of Medscape Medical News.

Pfizer and BioNTech announced the updated findings in a Nov. 4 press release.

A booster dose of the BA.4/BA.5-adapted bivalent vaccine is authorized for emergency use by the Food and Drug Administration for ages 5 years and older. The safety and tolerability profile of the Pfizer/BioNTech bivalent booster remains favorable and similar to the original COVID-19 vaccine, the company reported.

Until recently, the BA.5 Omicron variant was the dominant strain in the United States, but is now getting elbowed out by the subvariants BQ.1.1, BQ.1, and BA.4.6, which together make up almost 45% of the circulating virus.
 

Some skepticism

“It is important to note that these data are press-release level, which does not allow a view of the data totality,” Hana El Sahly, MD, professor of molecular virology and microbiology, Baylor College of Medicine, Houston, said in an interview.

“For example, there may be significant differences between the groups, and the release mentions at least one difference that is of importance: the interval since the last vaccination which often affects the response to subsequent boosting,” she said.

Dr. El Sahly added that the findings are not surprising. “In the short term, a variant-specific vaccine produces a higher level of antibody against the variant in the vaccine than the vaccines based on the ancestral strains.”

More researcher results are warranted. “These data do not indicate that these differences between the two vaccines translate into a meaningful clinical benefit at a population level,” Dr. El Sahly said.
 

An uncertain winter ahead

“As we head into the holiday season, we hope these updated data will encourage people to seek out a COVID-19 bivalent booster as soon as they are eligible in order to maintain high levels of protection against the widely circulating Omicron BA.4 and BA.5 sublineages,” Albert Bourla, Pfizer chairman and CEO, stated in the release.

The updated data from the Pfizer/BioNTech study are “all the more reason to get a booster, with added protection also versus BQ.1.1, which will soon become dominant in the U.S.,” Dr. Topol predicted.

It is unclear when the next surge will happen, as COVID-19 does not always follow a seasonal pattern, at least not yet, Dr. El Sahly said. “Regardless, it is reasonable to recommend additional vaccine doses to immunocompromised and frail or older persons. More importantly, influenza vaccination and being up to date on pneumococcal vaccines are highly recommended as soon as feasible, given the early and intense flu season.”

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

CHICAGO – The case for survival equipoise between an invasive or conservative strategy for managing patients with stable coronary disease and moderate or severe cardiac ischemia grew stronger with an additional 2.5 years of median follow-up of the landmark ISCHEMIA trial.

During a median follow-up of 5.7 years in ISCHEMIA-EXTEND – and as long as 7 years – patients randomized to an upfront invasive strategy regardless of their symptoms had an all-cause mortality rate of 12.7%, compared with a 13.4% rate in the patients randomized to the conservative, medication-based management strategy that employed revascularization only when the medical approach failed to resolve their angina. This survival difference fell far short of significance (adjusted hazard ratio, 1.00; 95% confidence interval, 0.85-1.18), solidifying a finding first seen in the main ISCHEMIA results when they came out 3 years before, in late 2019, Judith S. Hochman, MD, said at the American Heart Association scientific sessions.

Mitchel L. Zoler/MDedge News

The new results “provide evidence for patients with chronic coronary disease and their physicians as they decide whether to add invasive management to guideline-directed medical therapy,” concluded Dr. Hochman, professor and senior associate dean for clinical sciences at New York University Langone Health. Simultaneous with her report, the extended follow-up results also appeared in an article published online in Circulation.
 

Nil probability of a survival benefit

“The probability over 5.7 years that a patient’s risk of dying is lower with the invasive strategy is nil, which means: Go with the patient’s preference. Not undergoing revascularization is a reasonable strategy because there is no excess mortality,” Dr. Hochman said in an interview. The trial’s extended follow-up provides “much more robust evidence” for the neutral effect on survival. The investigators plan to further follow-up out to a maximum of 10 years to continue to monitor for a signal of a mortality difference.

Mitchel L. Zoler/MDedge News

“These findings might help physicians in shared decision-making as to whether to add invasive management to guideline-directed medical management in selected patients with chronic coronary artery disease and moderate or severe ischemia,” commented M. Cecilia Bahit, MD, designated discussant for the report and chief of cardiology for INECO Neurosciences in Rosario, Argentina.

The original ISCHEMIA results had also shown that invasive intervention can improve the quality of life in patients who have angina as a result of their coronary disease, but also showed “minimal benefits” from an invasive approach in asymptomatic patients, who comprised 35% of the study cohort of 5,179 patients.

While ISCHEMIA enrolled patients with moderate to severe coronary ischemia identified with noninvasive testing, it excluded certain patients for whom an invasive strategy is recommended, including those with unprotected left main coronary stenoses of at least 50%, a recent acute coronary syndrome event, a left ventricular ejection fraction of less than 35%, more advanced functional limitations from heart failure, or advanced chronic kidney disease.

Follow-up without adjudication

The extended follow-up included 4,825 patients from the initial cohort, with data collected from 4,540 patients. One limitation of the follow-up was that the cause of death was not adjudicated as it had been during the initial follow-up phase. It instead relied on unconfirmed information collected either from patients’ families or national databases. The demographics and clinical profiles of the study participants available for extended follow-up closely matched the entire original study cohort.

The additional follow-up also revealed a significant survival benefit from the invasive approach for cardiovascular deaths, with an incidence of 8.6% in the conservative arm and 6.4% in the invasive group, an adjusted 22% relative reduction in this outcome favoring the invasive strategy (95% CI, 0.63-0.96). This difference had appeared as a nonsignificant signal in the initial 3.2-year median follow-up.

However, this significant benefit from the invasive strategy was counterbalanced by a surprising and inexplicable increase in deaths from noncardiovascular causes in those managed with the invasive strategy. Noncardiovascular deaths occurred in 5.5% of those in the invasive arm and in 4.4% of those in the conservative arm, a significant adjusted 44% relative increase in this outcome associated with invasive management. Again, this difference was not as clearly apparent after the initial follow-up phase.

“The increase in noncardiovascular deaths with the invasive strategy surprisingly persisted over time and offset” the cardiovascular survival benefit from upfront invasive treatment, explained Dr. Hochman. A prior report from the investigators looked in depth at the noncardiovascular deaths during the initial follow-up phase and found that most of the excess was caused by malignancies, although why this happened in the invasively treated patients remains a mystery.

Staying alive is what patients care about

“I think that interventional cardiologists who favor an invasive strategy will be excited to see this significant reduction in cardiovascular deaths, but patients don’t care what they die from. What patients care about is whether they are dead or alive,” Dr. Hochman noted.

Mitchel L. Zoler/MDedge News

But B. Hadley Wilson, MD, an interventional cardiologist and vice president of the American College of Cardiology, had a somewhat different take on these findings.

“We need to consider the significant decrease in cardiovascular mortality, as we sort out the conundrum” of the increase in noncardiovascular deaths,” he said in an interview. “Hopefully, the 10-year outcomes will help answer this.”

But until more information is available, the ISCHEMIA and ISCHEMIA-EXTEND results have already helped advance the conversation that patients with stable coronary disease and their families have with clinicians about management decisions.

“I love that ISCHEMIA highlighted the importance of shared decision making and a heart team approach,” said Dr. Wilson, executive vice chair of the Sanger Heart & Vascular Institute of Atrium Health in Charlotte, N.C.
 

Anecdotally, ISCHEMIA reduced invasive management

After the initial ISCHEMIA results were published nearly 3 years ago, “I think use of invasive treatment for these patients has decreased, although I have seen no numbers” that document this, said Dr. Wilson. “I think most interventional cardiologists would say that ISCHEMIA has had an impact,” with fewer patients who match the trial’s enrollment criteria undergoing invasive management.

“Anecdotally, cardiologists are reviewing the ISCHEMIA data with their patients,” agreed Dr. Hochman, who added that no actual data have yet appeared to document this, nor do data yet document a change in the use of invasive management. “It takes time to measure the impact.”

To expedite the shared decision-making process for these patients, the ISCHEMIA researchers are planning to make available an app that will allow patients and physicians to enter clinical and demographic data and see a calculated estimate of their future cardiovascular disease risk and how amenable it may be to modification by invasive management, Dr. Hochman said. The app would be available on the ISCHEMIA study website in 2023.

ISCHEMIA and ISCHEMIA EXTEND received no commercial funding. Dr. Hochman and Dr. Wilson had no disclosures. Dr. Bahit has received honoraria from Behring, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, MSD, and Pfizer.






 

CHICAGO – The case for survival equipoise between an invasive or conservative strategy for managing patients with stable coronary disease and moderate or severe cardiac ischemia grew stronger with an additional 2.5 years of median follow-up of the landmark ISCHEMIA trial.

During a median follow-up of 5.7 years in ISCHEMIA-EXTEND – and as long as 7 years – patients randomized to an upfront invasive strategy regardless of their symptoms had an all-cause mortality rate of 12.7%, compared with a 13.4% rate in the patients randomized to the conservative, medication-based management strategy that employed revascularization only when the medical approach failed to resolve their angina. This survival difference fell far short of significance (adjusted hazard ratio, 1.00; 95% confidence interval, 0.85-1.18), solidifying a finding first seen in the main ISCHEMIA results when they came out 3 years before, in late 2019, Judith S. Hochman, MD, said at the American Heart Association scientific sessions.

Mitchel L. Zoler/MDedge News

The new results “provide evidence for patients with chronic coronary disease and their physicians as they decide whether to add invasive management to guideline-directed medical therapy,” concluded Dr. Hochman, professor and senior associate dean for clinical sciences at New York University Langone Health. Simultaneous with her report, the extended follow-up results also appeared in an article published online in Circulation.
 

Nil probability of a survival benefit

“The probability over 5.7 years that a patient’s risk of dying is lower with the invasive strategy is nil, which means: Go with the patient’s preference. Not undergoing revascularization is a reasonable strategy because there is no excess mortality,” Dr. Hochman said in an interview. The trial’s extended follow-up provides “much more robust evidence” for the neutral effect on survival. The investigators plan to further follow-up out to a maximum of 10 years to continue to monitor for a signal of a mortality difference.

Mitchel L. Zoler/MDedge News

“These findings might help physicians in shared decision-making as to whether to add invasive management to guideline-directed medical management in selected patients with chronic coronary artery disease and moderate or severe ischemia,” commented M. Cecilia Bahit, MD, designated discussant for the report and chief of cardiology for INECO Neurosciences in Rosario, Argentina.

The original ISCHEMIA results had also shown that invasive intervention can improve the quality of life in patients who have angina as a result of their coronary disease, but also showed “minimal benefits” from an invasive approach in asymptomatic patients, who comprised 35% of the study cohort of 5,179 patients.

While ISCHEMIA enrolled patients with moderate to severe coronary ischemia identified with noninvasive testing, it excluded certain patients for whom an invasive strategy is recommended, including those with unprotected left main coronary stenoses of at least 50%, a recent acute coronary syndrome event, a left ventricular ejection fraction of less than 35%, more advanced functional limitations from heart failure, or advanced chronic kidney disease.

Follow-up without adjudication

The extended follow-up included 4,825 patients from the initial cohort, with data collected from 4,540 patients. One limitation of the follow-up was that the cause of death was not adjudicated as it had been during the initial follow-up phase. It instead relied on unconfirmed information collected either from patients’ families or national databases. The demographics and clinical profiles of the study participants available for extended follow-up closely matched the entire original study cohort.

The additional follow-up also revealed a significant survival benefit from the invasive approach for cardiovascular deaths, with an incidence of 8.6% in the conservative arm and 6.4% in the invasive group, an adjusted 22% relative reduction in this outcome favoring the invasive strategy (95% CI, 0.63-0.96). This difference had appeared as a nonsignificant signal in the initial 3.2-year median follow-up.

However, this significant benefit from the invasive strategy was counterbalanced by a surprising and inexplicable increase in deaths from noncardiovascular causes in those managed with the invasive strategy. Noncardiovascular deaths occurred in 5.5% of those in the invasive arm and in 4.4% of those in the conservative arm, a significant adjusted 44% relative increase in this outcome associated with invasive management. Again, this difference was not as clearly apparent after the initial follow-up phase.

“The increase in noncardiovascular deaths with the invasive strategy surprisingly persisted over time and offset” the cardiovascular survival benefit from upfront invasive treatment, explained Dr. Hochman. A prior report from the investigators looked in depth at the noncardiovascular deaths during the initial follow-up phase and found that most of the excess was caused by malignancies, although why this happened in the invasively treated patients remains a mystery.

Staying alive is what patients care about

“I think that interventional cardiologists who favor an invasive strategy will be excited to see this significant reduction in cardiovascular deaths, but patients don’t care what they die from. What patients care about is whether they are dead or alive,” Dr. Hochman noted.

Mitchel L. Zoler/MDedge News

But B. Hadley Wilson, MD, an interventional cardiologist and vice president of the American College of Cardiology, had a somewhat different take on these findings.

“We need to consider the significant decrease in cardiovascular mortality, as we sort out the conundrum” of the increase in noncardiovascular deaths,” he said in an interview. “Hopefully, the 10-year outcomes will help answer this.”

But until more information is available, the ISCHEMIA and ISCHEMIA-EXTEND results have already helped advance the conversation that patients with stable coronary disease and their families have with clinicians about management decisions.

“I love that ISCHEMIA highlighted the importance of shared decision making and a heart team approach,” said Dr. Wilson, executive vice chair of the Sanger Heart & Vascular Institute of Atrium Health in Charlotte, N.C.
 

Anecdotally, ISCHEMIA reduced invasive management

After the initial ISCHEMIA results were published nearly 3 years ago, “I think use of invasive treatment for these patients has decreased, although I have seen no numbers” that document this, said Dr. Wilson. “I think most interventional cardiologists would say that ISCHEMIA has had an impact,” with fewer patients who match the trial’s enrollment criteria undergoing invasive management.

“Anecdotally, cardiologists are reviewing the ISCHEMIA data with their patients,” agreed Dr. Hochman, who added that no actual data have yet appeared to document this, nor do data yet document a change in the use of invasive management. “It takes time to measure the impact.”

To expedite the shared decision-making process for these patients, the ISCHEMIA researchers are planning to make available an app that will allow patients and physicians to enter clinical and demographic data and see a calculated estimate of their future cardiovascular disease risk and how amenable it may be to modification by invasive management, Dr. Hochman said. The app would be available on the ISCHEMIA study website in 2023.

ISCHEMIA and ISCHEMIA EXTEND received no commercial funding. Dr. Hochman and Dr. Wilson had no disclosures. Dr. Bahit has received honoraria from Behring, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, MSD, and Pfizer.






 

CHICAGO – The case for survival equipoise between an invasive or conservative strategy for managing patients with stable coronary disease and moderate or severe cardiac ischemia grew stronger with an additional 2.5 years of median follow-up of the landmark ISCHEMIA trial.

During a median follow-up of 5.7 years in ISCHEMIA-EXTEND – and as long as 7 years – patients randomized to an upfront invasive strategy regardless of their symptoms had an all-cause mortality rate of 12.7%, compared with a 13.4% rate in the patients randomized to the conservative, medication-based management strategy that employed revascularization only when the medical approach failed to resolve their angina. This survival difference fell far short of significance (adjusted hazard ratio, 1.00; 95% confidence interval, 0.85-1.18), solidifying a finding first seen in the main ISCHEMIA results when they came out 3 years before, in late 2019, Judith S. Hochman, MD, said at the American Heart Association scientific sessions.

Mitchel L. Zoler/MDedge News

The new results “provide evidence for patients with chronic coronary disease and their physicians as they decide whether to add invasive management to guideline-directed medical therapy,” concluded Dr. Hochman, professor and senior associate dean for clinical sciences at New York University Langone Health. Simultaneous with her report, the extended follow-up results also appeared in an article published online in Circulation.
 

Nil probability of a survival benefit

“The probability over 5.7 years that a patient’s risk of dying is lower with the invasive strategy is nil, which means: Go with the patient’s preference. Not undergoing revascularization is a reasonable strategy because there is no excess mortality,” Dr. Hochman said in an interview. The trial’s extended follow-up provides “much more robust evidence” for the neutral effect on survival. The investigators plan to further follow-up out to a maximum of 10 years to continue to monitor for a signal of a mortality difference.

Mitchel L. Zoler/MDedge News

“These findings might help physicians in shared decision-making as to whether to add invasive management to guideline-directed medical management in selected patients with chronic coronary artery disease and moderate or severe ischemia,” commented M. Cecilia Bahit, MD, designated discussant for the report and chief of cardiology for INECO Neurosciences in Rosario, Argentina.

The original ISCHEMIA results had also shown that invasive intervention can improve the quality of life in patients who have angina as a result of their coronary disease, but also showed “minimal benefits” from an invasive approach in asymptomatic patients, who comprised 35% of the study cohort of 5,179 patients.

While ISCHEMIA enrolled patients with moderate to severe coronary ischemia identified with noninvasive testing, it excluded certain patients for whom an invasive strategy is recommended, including those with unprotected left main coronary stenoses of at least 50%, a recent acute coronary syndrome event, a left ventricular ejection fraction of less than 35%, more advanced functional limitations from heart failure, or advanced chronic kidney disease.

Follow-up without adjudication

The extended follow-up included 4,825 patients from the initial cohort, with data collected from 4,540 patients. One limitation of the follow-up was that the cause of death was not adjudicated as it had been during the initial follow-up phase. It instead relied on unconfirmed information collected either from patients’ families or national databases. The demographics and clinical profiles of the study participants available for extended follow-up closely matched the entire original study cohort.

The additional follow-up also revealed a significant survival benefit from the invasive approach for cardiovascular deaths, with an incidence of 8.6% in the conservative arm and 6.4% in the invasive group, an adjusted 22% relative reduction in this outcome favoring the invasive strategy (95% CI, 0.63-0.96). This difference had appeared as a nonsignificant signal in the initial 3.2-year median follow-up.

However, this significant benefit from the invasive strategy was counterbalanced by a surprising and inexplicable increase in deaths from noncardiovascular causes in those managed with the invasive strategy. Noncardiovascular deaths occurred in 5.5% of those in the invasive arm and in 4.4% of those in the conservative arm, a significant adjusted 44% relative increase in this outcome associated with invasive management. Again, this difference was not as clearly apparent after the initial follow-up phase.

“The increase in noncardiovascular deaths with the invasive strategy surprisingly persisted over time and offset” the cardiovascular survival benefit from upfront invasive treatment, explained Dr. Hochman. A prior report from the investigators looked in depth at the noncardiovascular deaths during the initial follow-up phase and found that most of the excess was caused by malignancies, although why this happened in the invasively treated patients remains a mystery.

Staying alive is what patients care about

“I think that interventional cardiologists who favor an invasive strategy will be excited to see this significant reduction in cardiovascular deaths, but patients don’t care what they die from. What patients care about is whether they are dead or alive,” Dr. Hochman noted.

Mitchel L. Zoler/MDedge News

But B. Hadley Wilson, MD, an interventional cardiologist and vice president of the American College of Cardiology, had a somewhat different take on these findings.

“We need to consider the significant decrease in cardiovascular mortality, as we sort out the conundrum” of the increase in noncardiovascular deaths,” he said in an interview. “Hopefully, the 10-year outcomes will help answer this.”

But until more information is available, the ISCHEMIA and ISCHEMIA-EXTEND results have already helped advance the conversation that patients with stable coronary disease and their families have with clinicians about management decisions.

“I love that ISCHEMIA highlighted the importance of shared decision making and a heart team approach,” said Dr. Wilson, executive vice chair of the Sanger Heart & Vascular Institute of Atrium Health in Charlotte, N.C.
 

Anecdotally, ISCHEMIA reduced invasive management

After the initial ISCHEMIA results were published nearly 3 years ago, “I think use of invasive treatment for these patients has decreased, although I have seen no numbers” that document this, said Dr. Wilson. “I think most interventional cardiologists would say that ISCHEMIA has had an impact,” with fewer patients who match the trial’s enrollment criteria undergoing invasive management.

“Anecdotally, cardiologists are reviewing the ISCHEMIA data with their patients,” agreed Dr. Hochman, who added that no actual data have yet appeared to document this, nor do data yet document a change in the use of invasive management. “It takes time to measure the impact.”

To expedite the shared decision-making process for these patients, the ISCHEMIA researchers are planning to make available an app that will allow patients and physicians to enter clinical and demographic data and see a calculated estimate of their future cardiovascular disease risk and how amenable it may be to modification by invasive management, Dr. Hochman said. The app would be available on the ISCHEMIA study website in 2023.

ISCHEMIA and ISCHEMIA EXTEND received no commercial funding. Dr. Hochman and Dr. Wilson had no disclosures. Dr. Bahit has received honoraria from Behring, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, MSD, and Pfizer.






 

ORLANDO – Treatment with a renin-angiotensin system (RAS) inhibitor is widely accepted as standard practice for slowing progression of chronic kidney disease (CKD), but data have been inconsistent as to whether there is benefit to continuing RAS inhibition when patients develop advanced CKD, defined as an estimated glomerular filtration rate (eGFR) of less than 30 mL/min per 1.73 m².

Now, in STOP ACEi, a new multicenter, randomized trial of 411 patients, maintaining treatment with a RAS inhibitor in adults with advanced and progressive CKD did not cause a clinically relevant change in kidney function, or in the long-term rate of decline in kidney function, compared with stopping treatment, for 3 years.

People who continued RAS inhibitor treatment did not develop a significant or clinically relevant decrease in eGFR, the study’s primary outcome, both overall as well as in several prespecified subgroups compared with those who discontinued treatment, said Sunil Bhandari, MBChB, PhD, and associates, who presented the research in a poster at the annual meeting of the American Society of Nephrology.

“I hope these results will reassure clinicians to continue ACE inhibitors or ARBs” in patients with advanced CKD, “with their known beneficial cardiovascular effects,” Dr. Bhandari said in an interview.

The results were simultaneously published in the New England Journal of Medicine.
 

Similar eGFR levels after 3 years

While it’s clear that in patients with mild or moderate CKD, treatment with a RAS inhibitor, which includes angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs), reduces blood pressure, slows decline in eGFR, reduces proteinuria, and delays progression to advanced CKD, there has been little evidence that the use of RAS inhibitors benefits patients with advanced CKD.

Data from previous trials have been inconsistent regarding whether the use of RAS inhibitors is nephroprotective in patients with advanced CKD, say Dr. Bhandari, a nephrologist and professor at Hull York Medical School, Hull, England, and colleagues.

“Current guidelines do not provide specific advice on whether to continue or stop ACE inhibitors or ARBs for advanced chronic kidney disease,” they also note.

And so they decided to assess whether discontinuation of ACE inhibitors/ARBs could slow progression of CKD in patients with advanced CKD.

Three years after 206 study participants stopped RAS inhibitor treatment, the least-squares mean eGFR was 12.6 mL/min per 1.73m² in the discontinuation group and 13.3 mL/min per 1.73 m² in the 205 patients in the continuation group, a difference that was not significant.

In addition to the primary outcome, 62% of patients who stopped RAS inhibitor treatment and 56% of those who continued developed end-stage kidney disease or required renal-replacement therapy, which translated into an adjusted hazard ratio of 1.28 for this outcome among those who discontinued compared with those who continued, which was just short of significance (95% CI, 0.99-1.65).

The two study groups also showed no significant differences in the 3-year incidence of hospitalization for any reason, cardiovascular events, or deaths. The two groups also showed no meaningful differences in various domains of quality of life and no differences in serious adverse effects.
 

Participants had an eGFR less than 30 mL/min per 1.73 m²

The study ran at 39 United Kingdom centers in 2014-2019. Investigators enrolled adults with an eGFR of less than 30 mL/min per 1.73 m² who were not on dialysis and had not received a kidney transplant. In addition, all enrolled patients had to have an annual drop in eGFR of more than 2 mL/min per 1.73 m² during the prior 2 years and had to have been on treatment with at least one RAS inhibitor for more than 6 months.

The randomization protocol insured balanced distribution of subjects between the two study arms by age, eGFR, presence of diabetes, and level of proteinuria, among other factors. The study design also mandated that participants maintain a blood pressure of no more than 140/85 mm Hg.

Those who discontinued RAS-inhibitor treatment could receive any guideline-recommended antihypertensive agent that was not a RAS inhibitor, although adding a RAS inhibitor was permitted as a last treatment resort.

People in the maintenance group could receive whichever additional antihypertensive agents their treating clinicians deemed necessary for maintaining the target blood pressure.

The enrolled population was a median age of 63 years old and 68% were men. Their average eGFR at baseline was 18 mL/min per 1.73 m², and 118 (29%) had an eGFR of less than 15 mL/min per 1.73 m². Their median level of proteinuria was 115 mg/mmol (about 1,018 mg/g). Diabetes was prevalent in 37%, and 58% of participants were taking at least three antihypertensive medications at entry.

Among the study’s limitations, the researchers cited the open-label design, which may have affected clinical care and the tally of subjective endpoints, including quality of life and exercise capacity. Also, because the study enrolled people who were on a RAS inhibitor at the time of randomization, it did not include anyone who had already discontinued these agents.
 

Continue RAS inhibitors in advanced CKD for best outcomes

Dr. Bhandari and colleagues note that in a large observational trial published in January 2021, Swedish researchers found an increase in the incidence of major cardiovascular events and death among patients with advanced CKD who had discontinued RAS inhibitors.

But they observe, “Our trial did not have sufficient power to investigate the effect of the discontinuation of RAS inhibitors on cardiovascular events or mortality. However, because our findings are consistent with a lack of advantage for such discontinuation with respect to kidney function, there is little rationale to conduct a larger randomized trial to investigate cardiovascular safety.”

“Our findings do not support the hypothesis that the discontinuation of RAS inhibitors in patients with advanced and progressive chronic kidney disease would improve kidney function, quality of life, or exercise capacity.”

“The results of this trial will inform future clinical practice worldwide and guideline recommendations,” they conclude.

STOP ACEi received no commercial funding. Dr. Bhandari has reported no relevant financial relationships.

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

ORLANDO – Treatment with a renin-angiotensin system (RAS) inhibitor is widely accepted as standard practice for slowing progression of chronic kidney disease (CKD), but data have been inconsistent as to whether there is benefit to continuing RAS inhibition when patients develop advanced CKD, defined as an estimated glomerular filtration rate (eGFR) of less than 30 mL/min per 1.73 m².

Now, in STOP ACEi, a new multicenter, randomized trial of 411 patients, maintaining treatment with a RAS inhibitor in adults with advanced and progressive CKD did not cause a clinically relevant change in kidney function, or in the long-term rate of decline in kidney function, compared with stopping treatment, for 3 years.

People who continued RAS inhibitor treatment did not develop a significant or clinically relevant decrease in eGFR, the study’s primary outcome, both overall as well as in several prespecified subgroups compared with those who discontinued treatment, said Sunil Bhandari, MBChB, PhD, and associates, who presented the research in a poster at the annual meeting of the American Society of Nephrology.

“I hope these results will reassure clinicians to continue ACE inhibitors or ARBs” in patients with advanced CKD, “with their known beneficial cardiovascular effects,” Dr. Bhandari said in an interview.

The results were simultaneously published in the New England Journal of Medicine.
 

Similar eGFR levels after 3 years

While it’s clear that in patients with mild or moderate CKD, treatment with a RAS inhibitor, which includes angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs), reduces blood pressure, slows decline in eGFR, reduces proteinuria, and delays progression to advanced CKD, there has been little evidence that the use of RAS inhibitors benefits patients with advanced CKD.

Data from previous trials have been inconsistent regarding whether the use of RAS inhibitors is nephroprotective in patients with advanced CKD, say Dr. Bhandari, a nephrologist and professor at Hull York Medical School, Hull, England, and colleagues.

“Current guidelines do not provide specific advice on whether to continue or stop ACE inhibitors or ARBs for advanced chronic kidney disease,” they also note.

And so they decided to assess whether discontinuation of ACE inhibitors/ARBs could slow progression of CKD in patients with advanced CKD.

Three years after 206 study participants stopped RAS inhibitor treatment, the least-squares mean eGFR was 12.6 mL/min per 1.73m² in the discontinuation group and 13.3 mL/min per 1.73 m² in the 205 patients in the continuation group, a difference that was not significant.

In addition to the primary outcome, 62% of patients who stopped RAS inhibitor treatment and 56% of those who continued developed end-stage kidney disease or required renal-replacement therapy, which translated into an adjusted hazard ratio of 1.28 for this outcome among those who discontinued compared with those who continued, which was just short of significance (95% CI, 0.99-1.65).

The two study groups also showed no significant differences in the 3-year incidence of hospitalization for any reason, cardiovascular events, or deaths. The two groups also showed no meaningful differences in various domains of quality of life and no differences in serious adverse effects.
 

Participants had an eGFR less than 30 mL/min per 1.73 m²

The study ran at 39 United Kingdom centers in 2014-2019. Investigators enrolled adults with an eGFR of less than 30 mL/min per 1.73 m² who were not on dialysis and had not received a kidney transplant. In addition, all enrolled patients had to have an annual drop in eGFR of more than 2 mL/min per 1.73 m² during the prior 2 years and had to have been on treatment with at least one RAS inhibitor for more than 6 months.

The randomization protocol insured balanced distribution of subjects between the two study arms by age, eGFR, presence of diabetes, and level of proteinuria, among other factors. The study design also mandated that participants maintain a blood pressure of no more than 140/85 mm Hg.

Those who discontinued RAS-inhibitor treatment could receive any guideline-recommended antihypertensive agent that was not a RAS inhibitor, although adding a RAS inhibitor was permitted as a last treatment resort.

People in the maintenance group could receive whichever additional antihypertensive agents their treating clinicians deemed necessary for maintaining the target blood pressure.

The enrolled population was a median age of 63 years old and 68% were men. Their average eGFR at baseline was 18 mL/min per 1.73 m², and 118 (29%) had an eGFR of less than 15 mL/min per 1.73 m². Their median level of proteinuria was 115 mg/mmol (about 1,018 mg/g). Diabetes was prevalent in 37%, and 58% of participants were taking at least three antihypertensive medications at entry.

Among the study’s limitations, the researchers cited the open-label design, which may have affected clinical care and the tally of subjective endpoints, including quality of life and exercise capacity. Also, because the study enrolled people who were on a RAS inhibitor at the time of randomization, it did not include anyone who had already discontinued these agents.
 

Continue RAS inhibitors in advanced CKD for best outcomes

Dr. Bhandari and colleagues note that in a large observational trial published in January 2021, Swedish researchers found an increase in the incidence of major cardiovascular events and death among patients with advanced CKD who had discontinued RAS inhibitors.

But they observe, “Our trial did not have sufficient power to investigate the effect of the discontinuation of RAS inhibitors on cardiovascular events or mortality. However, because our findings are consistent with a lack of advantage for such discontinuation with respect to kidney function, there is little rationale to conduct a larger randomized trial to investigate cardiovascular safety.”

“Our findings do not support the hypothesis that the discontinuation of RAS inhibitors in patients with advanced and progressive chronic kidney disease would improve kidney function, quality of life, or exercise capacity.”

“The results of this trial will inform future clinical practice worldwide and guideline recommendations,” they conclude.

STOP ACEi received no commercial funding. Dr. Bhandari has reported no relevant financial relationships.

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

ORLANDO – Treatment with a renin-angiotensin system (RAS) inhibitor is widely accepted as standard practice for slowing progression of chronic kidney disease (CKD), but data have been inconsistent as to whether there is benefit to continuing RAS inhibition when patients develop advanced CKD, defined as an estimated glomerular filtration rate (eGFR) of less than 30 mL/min per 1.73 m².

Now, in STOP ACEi, a new multicenter, randomized trial of 411 patients, maintaining treatment with a RAS inhibitor in adults with advanced and progressive CKD did not cause a clinically relevant change in kidney function, or in the long-term rate of decline in kidney function, compared with stopping treatment, for 3 years.

People who continued RAS inhibitor treatment did not develop a significant or clinically relevant decrease in eGFR, the study’s primary outcome, both overall as well as in several prespecified subgroups compared with those who discontinued treatment, said Sunil Bhandari, MBChB, PhD, and associates, who presented the research in a poster at the annual meeting of the American Society of Nephrology.

“I hope these results will reassure clinicians to continue ACE inhibitors or ARBs” in patients with advanced CKD, “with their known beneficial cardiovascular effects,” Dr. Bhandari said in an interview.

The results were simultaneously published in the New England Journal of Medicine.
 

Similar eGFR levels after 3 years

While it’s clear that in patients with mild or moderate CKD, treatment with a RAS inhibitor, which includes angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs), reduces blood pressure, slows decline in eGFR, reduces proteinuria, and delays progression to advanced CKD, there has been little evidence that the use of RAS inhibitors benefits patients with advanced CKD.

Data from previous trials have been inconsistent regarding whether the use of RAS inhibitors is nephroprotective in patients with advanced CKD, say Dr. Bhandari, a nephrologist and professor at Hull York Medical School, Hull, England, and colleagues.

“Current guidelines do not provide specific advice on whether to continue or stop ACE inhibitors or ARBs for advanced chronic kidney disease,” they also note.

And so they decided to assess whether discontinuation of ACE inhibitors/ARBs could slow progression of CKD in patients with advanced CKD.

Three years after 206 study participants stopped RAS inhibitor treatment, the least-squares mean eGFR was 12.6 mL/min per 1.73m² in the discontinuation group and 13.3 mL/min per 1.73 m² in the 205 patients in the continuation group, a difference that was not significant.

In addition to the primary outcome, 62% of patients who stopped RAS inhibitor treatment and 56% of those who continued developed end-stage kidney disease or required renal-replacement therapy, which translated into an adjusted hazard ratio of 1.28 for this outcome among those who discontinued compared with those who continued, which was just short of significance (95% CI, 0.99-1.65).

The two study groups also showed no significant differences in the 3-year incidence of hospitalization for any reason, cardiovascular events, or deaths. The two groups also showed no meaningful differences in various domains of quality of life and no differences in serious adverse effects.
 

Participants had an eGFR less than 30 mL/min per 1.73 m²

The study ran at 39 United Kingdom centers in 2014-2019. Investigators enrolled adults with an eGFR of less than 30 mL/min per 1.73 m² who were not on dialysis and had not received a kidney transplant. In addition, all enrolled patients had to have an annual drop in eGFR of more than 2 mL/min per 1.73 m² during the prior 2 years and had to have been on treatment with at least one RAS inhibitor for more than 6 months.

The randomization protocol insured balanced distribution of subjects between the two study arms by age, eGFR, presence of diabetes, and level of proteinuria, among other factors. The study design also mandated that participants maintain a blood pressure of no more than 140/85 mm Hg.

Those who discontinued RAS-inhibitor treatment could receive any guideline-recommended antihypertensive agent that was not a RAS inhibitor, although adding a RAS inhibitor was permitted as a last treatment resort.

People in the maintenance group could receive whichever additional antihypertensive agents their treating clinicians deemed necessary for maintaining the target blood pressure.

The enrolled population was a median age of 63 years old and 68% were men. Their average eGFR at baseline was 18 mL/min per 1.73 m², and 118 (29%) had an eGFR of less than 15 mL/min per 1.73 m². Their median level of proteinuria was 115 mg/mmol (about 1,018 mg/g). Diabetes was prevalent in 37%, and 58% of participants were taking at least three antihypertensive medications at entry.

Among the study’s limitations, the researchers cited the open-label design, which may have affected clinical care and the tally of subjective endpoints, including quality of life and exercise capacity. Also, because the study enrolled people who were on a RAS inhibitor at the time of randomization, it did not include anyone who had already discontinued these agents.
 

Continue RAS inhibitors in advanced CKD for best outcomes

Dr. Bhandari and colleagues note that in a large observational trial published in January 2021, Swedish researchers found an increase in the incidence of major cardiovascular events and death among patients with advanced CKD who had discontinued RAS inhibitors.

But they observe, “Our trial did not have sufficient power to investigate the effect of the discontinuation of RAS inhibitors on cardiovascular events or mortality. However, because our findings are consistent with a lack of advantage for such discontinuation with respect to kidney function, there is little rationale to conduct a larger randomized trial to investigate cardiovascular safety.”

“Our findings do not support the hypothesis that the discontinuation of RAS inhibitors in patients with advanced and progressive chronic kidney disease would improve kidney function, quality of life, or exercise capacity.”

“The results of this trial will inform future clinical practice worldwide and guideline recommendations,” they conclude.

STOP ACEi received no commercial funding. Dr. Bhandari has reported no relevant financial relationships.

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

The Food and Drug Administration has expanded the indication for tenofovir alafenamide (Vemlidy) to children aged 12 years and older with chronic hepatitis B virus (HBV) infection with compensated liver disease, the drug’s manufacturer has announced.

The approval in the pediatric patient population was supported by 24-week data from a phase 2 clinical trial comparing treatment with tenofovir alafenamide (25 mg once daily) with placebo in 70 treatment-naive and treatment-experienced patients aged 12-18 years weighing at least 35 kg.

The study met its primary endpoint of percentage of patients with HBV DNA levels less than 20 IU/mL at 24 weeks of therapy, Gilead Sciences said in a press release.

Overall, 10 of 47 (21%) patients treated with tenofovir alafenamide achieved HBV DNA less than 20 IU/mL at 24 weeks, compared with 0 of 23 (0%) treated with placebo.

The rates of serum ALT normalization were higher with tenofovir alafenamide than with placebo (44% vs 0%).

The mean percent changes in bone mineral density (BMD) from baseline to 24 weeks were numerically similar for tenofovir alafenamide– and placebo-treated patients (2.4% and 1.9% for lumbar spine, and 1.5% and 1.9% for whole body, respectively).

The mean changes from baseline BMD z scores were –0.03 and –0.09 for lumbar spine, and –0.05 and –0.01 for whole body, for tenofovir alafenamide and placebo groups, respectively.

The FDA initially approved the nucleoside analog reverse transcriptase inhibitor in 2016 for adults with chronic HBV.

The drug was approved in Europe in 2017 for chronic HBV infection in adults and adolescents aged 12 years and older weighing at least 35 kg.

Tenofovir alafenamide carries a boxed warning citing risks for lactic acidosis/severe hepatomegaly with steatosis and posttreatment severe acute exacerbation of HBV.

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

The Food and Drug Administration has expanded the indication for tenofovir alafenamide (Vemlidy) to children aged 12 years and older with chronic hepatitis B virus (HBV) infection with compensated liver disease, the drug’s manufacturer has announced.

The approval in the pediatric patient population was supported by 24-week data from a phase 2 clinical trial comparing treatment with tenofovir alafenamide (25 mg once daily) with placebo in 70 treatment-naive and treatment-experienced patients aged 12-18 years weighing at least 35 kg.

The study met its primary endpoint of percentage of patients with HBV DNA levels less than 20 IU/mL at 24 weeks of therapy, Gilead Sciences said in a press release.

Overall, 10 of 47 (21%) patients treated with tenofovir alafenamide achieved HBV DNA less than 20 IU/mL at 24 weeks, compared with 0 of 23 (0%) treated with placebo.

The rates of serum ALT normalization were higher with tenofovir alafenamide than with placebo (44% vs 0%).

The mean percent changes in bone mineral density (BMD) from baseline to 24 weeks were numerically similar for tenofovir alafenamide– and placebo-treated patients (2.4% and 1.9% for lumbar spine, and 1.5% and 1.9% for whole body, respectively).

The mean changes from baseline BMD z scores were –0.03 and –0.09 for lumbar spine, and –0.05 and –0.01 for whole body, for tenofovir alafenamide and placebo groups, respectively.

The FDA initially approved the nucleoside analog reverse transcriptase inhibitor in 2016 for adults with chronic HBV.

The drug was approved in Europe in 2017 for chronic HBV infection in adults and adolescents aged 12 years and older weighing at least 35 kg.

Tenofovir alafenamide carries a boxed warning citing risks for lactic acidosis/severe hepatomegaly with steatosis and posttreatment severe acute exacerbation of HBV.

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

The Food and Drug Administration has expanded the indication for tenofovir alafenamide (Vemlidy) to children aged 12 years and older with chronic hepatitis B virus (HBV) infection with compensated liver disease, the drug’s manufacturer has announced.

The approval in the pediatric patient population was supported by 24-week data from a phase 2 clinical trial comparing treatment with tenofovir alafenamide (25 mg once daily) with placebo in 70 treatment-naive and treatment-experienced patients aged 12-18 years weighing at least 35 kg.

The study met its primary endpoint of percentage of patients with HBV DNA levels less than 20 IU/mL at 24 weeks of therapy, Gilead Sciences said in a press release.

Overall, 10 of 47 (21%) patients treated with tenofovir alafenamide achieved HBV DNA less than 20 IU/mL at 24 weeks, compared with 0 of 23 (0%) treated with placebo.

The rates of serum ALT normalization were higher with tenofovir alafenamide than with placebo (44% vs 0%).

The mean percent changes in bone mineral density (BMD) from baseline to 24 weeks were numerically similar for tenofovir alafenamide– and placebo-treated patients (2.4% and 1.9% for lumbar spine, and 1.5% and 1.9% for whole body, respectively).

The mean changes from baseline BMD z scores were –0.03 and –0.09 for lumbar spine, and –0.05 and –0.01 for whole body, for tenofovir alafenamide and placebo groups, respectively.

The FDA initially approved the nucleoside analog reverse transcriptase inhibitor in 2016 for adults with chronic HBV.

The drug was approved in Europe in 2017 for chronic HBV infection in adults and adolescents aged 12 years and older weighing at least 35 kg.

Tenofovir alafenamide carries a boxed warning citing risks for lactic acidosis/severe hepatomegaly with steatosis and posttreatment severe acute exacerbation of HBV.

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

LAS VEGAS – Acne is a barrier-deficient disorder, and good skin care with over-the-counter products can improve this barrier and increase adherence to prescription medications, Hilary E. Baldwin, MD, of Rutgers Robert Wood Johnson Medical Center, New Brunswick, N.J., said in a presentation at Medscape Live’s annual Las Vegas Dermatology Seminar.

In some cases, the use of good-quality over-the -counter skin care products can improve acne without prescription treatment, said Dr. Baldwin, who is medical director of the Acne Treatment and Research Center, New York. Good skin care can enhance the effects of prescription medication by decreasing side effects such as inflammation, pain, and erythema, and improving compliance; and use of OTC products has not been shown to interfere with the efficacy of prescription products, she noted.

However, patient education about OTC products is key, she said. In particular, “cleansers are a double-edged sword,” Dr. Baldwin emphasized.

Cleansing is important to preserve barrier function, but “there is a risk of skin damage” if cleansers are too harsh, she said. The goal is to remove dirt, oils, and bacteria without disrupting the lipids, proteins, and normal flora that keep skin healthy, and to avoid altering pH, she added.

Key considerations for OTC cleansers include surfactants, pH, and patient preferences, Dr. Baldwin said.

Surfactants, the main components of OTC cleansers, can do more harm than good in some cases. Surfactants break down impurities on the skin surface, but not all are created equal, and some may cause skin irritation, she explained.

Surfactants fall into four categories: nonionic (no charge), anionic (negative charge), cationic (positive charge), and amphoteric (dual charge). Of these, cationic surfactants have the highest level of antimicrobial activity.

Many patients with acne seek out antibacterial cleansers, but many of these products have a high pH, which can inhibit healthy skin function and promote inflammation, Dr. Baldwin noted.

The right OTC skin care products can normalize pH, which promotes repair of the skin barrier and reduces inflammation, she said. While some products are labeled as “gentle,” they may have a high pH, and many products don’t list a pH, Dr. Baldwin pointed out. Many antibacterial products have pH levels in the 10-12 range, while true soaps fall in the 9-10 range, and hydrating liquid cleansers often land in the 5-7 range, she said.

“Most of our patients don’t know what ingredients to look for” in a cleanser, she noted. However, data show that a majority of patients prefer a foaming cleanser, enjoy the face-washing experience – and wash their faces at least twice a day, with a range of products including bath soap, said Dr. Baldwin. Consequently, “educate your patient about moisturizing,” she advised.

For patients with greasy or oily skin, Dr. Baldwin recommends lipid-free foaming cleansers, such as those with ceramides or glycerin. For patients with dry, irritated acne, she advises once-daily washing only, without cleansing devices, which includes washcloths, she said. Look for hydrating cleansers that are nonfoaming or slightly foaming for these patients, she added.

Another tip for patients is to remind them that “sebum is not a moisturizer,” said Dr. Baldwin. Acne patients may still need moisturizers, especially if they experience dry skin as a side effect of their acne medication, but finding the right fit can be a challenge requiring some trial and error, she noted.

OTC products for rosacea

Dr. Baldwin also addressed the use of OTC products for patients with rosacea. For cleansers, she recommends the same hydrating, nonfoaming categories as for her acne patients, with a once-daily, no-device regimen. She advises rosacea patients to avoid pure humectants for moisturizing and noted that silicone-based products are often the least irritating.

Seek moisturizers with ceramides, hyaluronic acid, glycerin, or niacinamide, she said. Data have shown that effective moisturization improves the ability of patients with rosacea to use and adhere to their prescription medications, Dr. Baldwin emphasized. Moisturizers also can make the medication more effective by enhancing the penetration of products such as azelaic acid, she added.

No acne or rosacea visit is complete until overall skin care has been discussed, Dr. Baldwin said.

Dr. Baldwin disclosed serving as a consultant or adviser for Almirall, EPI Health, Galderma, La Roche Posay, Ortho Dermatologics, Sun, and Vyne; and serving as a speaker or member of the speakers’ bureau for Almirall, Galderma, La Roche Posay, Ortho Dermatologics, and Sun. MedscapeLive and this news organization are owned by the same parent company.

LAS VEGAS – Acne is a barrier-deficient disorder, and good skin care with over-the-counter products can improve this barrier and increase adherence to prescription medications, Hilary E. Baldwin, MD, of Rutgers Robert Wood Johnson Medical Center, New Brunswick, N.J., said in a presentation at Medscape Live’s annual Las Vegas Dermatology Seminar.

In some cases, the use of good-quality over-the -counter skin care products can improve acne without prescription treatment, said Dr. Baldwin, who is medical director of the Acne Treatment and Research Center, New York. Good skin care can enhance the effects of prescription medication by decreasing side effects such as inflammation, pain, and erythema, and improving compliance; and use of OTC products has not been shown to interfere with the efficacy of prescription products, she noted.

However, patient education about OTC products is key, she said. In particular, “cleansers are a double-edged sword,” Dr. Baldwin emphasized.

Cleansing is important to preserve barrier function, but “there is a risk of skin damage” if cleansers are too harsh, she said. The goal is to remove dirt, oils, and bacteria without disrupting the lipids, proteins, and normal flora that keep skin healthy, and to avoid altering pH, she added.

Key considerations for OTC cleansers include surfactants, pH, and patient preferences, Dr. Baldwin said.

Surfactants, the main components of OTC cleansers, can do more harm than good in some cases. Surfactants break down impurities on the skin surface, but not all are created equal, and some may cause skin irritation, she explained.

Surfactants fall into four categories: nonionic (no charge), anionic (negative charge), cationic (positive charge), and amphoteric (dual charge). Of these, cationic surfactants have the highest level of antimicrobial activity.

Many patients with acne seek out antibacterial cleansers, but many of these products have a high pH, which can inhibit healthy skin function and promote inflammation, Dr. Baldwin noted.

The right OTC skin care products can normalize pH, which promotes repair of the skin barrier and reduces inflammation, she said. While some products are labeled as “gentle,” they may have a high pH, and many products don’t list a pH, Dr. Baldwin pointed out. Many antibacterial products have pH levels in the 10-12 range, while true soaps fall in the 9-10 range, and hydrating liquid cleansers often land in the 5-7 range, she said.

“Most of our patients don’t know what ingredients to look for” in a cleanser, she noted. However, data show that a majority of patients prefer a foaming cleanser, enjoy the face-washing experience – and wash their faces at least twice a day, with a range of products including bath soap, said Dr. Baldwin. Consequently, “educate your patient about moisturizing,” she advised.

For patients with greasy or oily skin, Dr. Baldwin recommends lipid-free foaming cleansers, such as those with ceramides or glycerin. For patients with dry, irritated acne, she advises once-daily washing only, without cleansing devices, which includes washcloths, she said. Look for hydrating cleansers that are nonfoaming or slightly foaming for these patients, she added.

Another tip for patients is to remind them that “sebum is not a moisturizer,” said Dr. Baldwin. Acne patients may still need moisturizers, especially if they experience dry skin as a side effect of their acne medication, but finding the right fit can be a challenge requiring some trial and error, she noted.

OTC products for rosacea

Dr. Baldwin also addressed the use of OTC products for patients with rosacea. For cleansers, she recommends the same hydrating, nonfoaming categories as for her acne patients, with a once-daily, no-device regimen. She advises rosacea patients to avoid pure humectants for moisturizing and noted that silicone-based products are often the least irritating.

Seek moisturizers with ceramides, hyaluronic acid, glycerin, or niacinamide, she said. Data have shown that effective moisturization improves the ability of patients with rosacea to use and adhere to their prescription medications, Dr. Baldwin emphasized. Moisturizers also can make the medication more effective by enhancing the penetration of products such as azelaic acid, she added.

No acne or rosacea visit is complete until overall skin care has been discussed, Dr. Baldwin said.

Dr. Baldwin disclosed serving as a consultant or adviser for Almirall, EPI Health, Galderma, La Roche Posay, Ortho Dermatologics, Sun, and Vyne; and serving as a speaker or member of the speakers’ bureau for Almirall, Galderma, La Roche Posay, Ortho Dermatologics, and Sun. MedscapeLive and this news organization are owned by the same parent company.

LAS VEGAS – Acne is a barrier-deficient disorder, and good skin care with over-the-counter products can improve this barrier and increase adherence to prescription medications, Hilary E. Baldwin, MD, of Rutgers Robert Wood Johnson Medical Center, New Brunswick, N.J., said in a presentation at Medscape Live’s annual Las Vegas Dermatology Seminar.

In some cases, the use of good-quality over-the -counter skin care products can improve acne without prescription treatment, said Dr. Baldwin, who is medical director of the Acne Treatment and Research Center, New York. Good skin care can enhance the effects of prescription medication by decreasing side effects such as inflammation, pain, and erythema, and improving compliance; and use of OTC products has not been shown to interfere with the efficacy of prescription products, she noted.

However, patient education about OTC products is key, she said. In particular, “cleansers are a double-edged sword,” Dr. Baldwin emphasized.

Cleansing is important to preserve barrier function, but “there is a risk of skin damage” if cleansers are too harsh, she said. The goal is to remove dirt, oils, and bacteria without disrupting the lipids, proteins, and normal flora that keep skin healthy, and to avoid altering pH, she added.

Key considerations for OTC cleansers include surfactants, pH, and patient preferences, Dr. Baldwin said.

Surfactants, the main components of OTC cleansers, can do more harm than good in some cases. Surfactants break down impurities on the skin surface, but not all are created equal, and some may cause skin irritation, she explained.

Surfactants fall into four categories: nonionic (no charge), anionic (negative charge), cationic (positive charge), and amphoteric (dual charge). Of these, cationic surfactants have the highest level of antimicrobial activity.

Many patients with acne seek out antibacterial cleansers, but many of these products have a high pH, which can inhibit healthy skin function and promote inflammation, Dr. Baldwin noted.

The right OTC skin care products can normalize pH, which promotes repair of the skin barrier and reduces inflammation, she said. While some products are labeled as “gentle,” they may have a high pH, and many products don’t list a pH, Dr. Baldwin pointed out. Many antibacterial products have pH levels in the 10-12 range, while true soaps fall in the 9-10 range, and hydrating liquid cleansers often land in the 5-7 range, she said.

“Most of our patients don’t know what ingredients to look for” in a cleanser, she noted. However, data show that a majority of patients prefer a foaming cleanser, enjoy the face-washing experience – and wash their faces at least twice a day, with a range of products including bath soap, said Dr. Baldwin. Consequently, “educate your patient about moisturizing,” she advised.

For patients with greasy or oily skin, Dr. Baldwin recommends lipid-free foaming cleansers, such as those with ceramides or glycerin. For patients with dry, irritated acne, she advises once-daily washing only, without cleansing devices, which includes washcloths, she said. Look for hydrating cleansers that are nonfoaming or slightly foaming for these patients, she added.

Another tip for patients is to remind them that “sebum is not a moisturizer,” said Dr. Baldwin. Acne patients may still need moisturizers, especially if they experience dry skin as a side effect of their acne medication, but finding the right fit can be a challenge requiring some trial and error, she noted.

OTC products for rosacea

Dr. Baldwin also addressed the use of OTC products for patients with rosacea. For cleansers, she recommends the same hydrating, nonfoaming categories as for her acne patients, with a once-daily, no-device regimen. She advises rosacea patients to avoid pure humectants for moisturizing and noted that silicone-based products are often the least irritating.

Seek moisturizers with ceramides, hyaluronic acid, glycerin, or niacinamide, she said. Data have shown that effective moisturization improves the ability of patients with rosacea to use and adhere to their prescription medications, Dr. Baldwin emphasized. Moisturizers also can make the medication more effective by enhancing the penetration of products such as azelaic acid, she added.

No acne or rosacea visit is complete until overall skin care has been discussed, Dr. Baldwin said.

Dr. Baldwin disclosed serving as a consultant or adviser for Almirall, EPI Health, Galderma, La Roche Posay, Ortho Dermatologics, Sun, and Vyne; and serving as a speaker or member of the speakers’ bureau for Almirall, Galderma, La Roche Posay, Ortho Dermatologics, and Sun. MedscapeLive and this news organization are owned by the same parent company.

CHICAGO – Treatment with the investigational CRISPR-Cas9 gene-editing therapy, NTLA-2001, led to rapid responses in patients with transthyretin (TTR) amyloidosis with cardiomyopathy (ATTR-CM), interim phase 1 results show.

Serum levels of the disease-causing TTR protein were reduced by at least 90% at day 28 with a single infusion of NTLA-2001 at two different doses, with reductions sustained across 4-6 months’ follow-up.

NTLA-2001 was generally well-tolerated, and the results were similar in patients with New York Heart Association (NYHA) class I-III heart failure.

“These data further support and extend the early findings demonstrating the promise of CRISPR-based in vivo genome editing in humans,” said Julian Gillmore, MD, PhD, MBBS, who is leading the study at University College London.

“More specifically, the deep TTR reductions observed in patients with ATTR amyloidosis in this study provide a real possibility of genuine clinical improvement in a condition that has hitherto been ultimately progressive and invariably fatal,” he said.

The results were reported in a late-breaking session at the American Heart Association scientific sessions.

Mutations in the TTR gene and age-related changes in the stability of the TTR protein can cause misfolding of the TTR protein, resulting in amyloid deposits in skin and myocardial tissues.

An estimated 50,000 people worldwide are thought to have hereditary ATTR and up to 500,000 to have wild-type ATTR amyloidosis. Amyloid cardiomyopathy is underdiagnosed and fatal in 3-10 years without treatment. Current treatment options only slow progression and require lifelong administration, he said.

Results reported last year from the polyneuropathy arm of the study were hailed as a breakthrough and further proof-of-concept that CRISPR could be used to treat other diseases

CRISPR gene editing has shown success, for example, in beta-thalassemia and sickle cell disease but involved stem cells extracted from patients’ bone marrow, edited in the lab, and then replaced.

NTLA-2001 (Intellia Therapeutics/Regeneron) is an in vivo treatment that uses lipid nanoparticles containing messenger RNA for Cas9 and a single-guide RNA targeting TTR in the liver, where it’s almost exclusively produced.

The new analysis included 12 patients with heart failure: 3 in NYHA  class I-II and 6 in NYHA class III who received a single dose of NTLA-2001 at 0.7 mg/kg, while the remaining 3 patients in NYHA class I-II received a single dose of 1.0 mg/kg.

During follow-up out to 6 months, TTR reductions averaged:

• 93% in the 0.7 mg/kg NYHA I-II group at 6 months.
• 94% in the 0.7 mg/kg NYHA III group at 4 months.
• 92% in the 1.0 mg/kg NYHA I-II group at 4 months.

Eight patients reported mild or moderate adverse events, and two patients experienced transient infusion reactions, including one grade 3 reaction in the 0.7 mg/kg NYHA class III group that resolved without clinical consequence. This group was expanded to six patients per study protocol. No additional treatment-related adverse events higher than grade 1 were reported, and no further dose escalation was undertaken, Dr. Gillmore reported.

There were no clinically relevant laboratory findings; one patient had a transient grade 1 liver enzyme elevation.

One disadvantage of CRISPR is the potential for off-target effects, but Dr. Gillmore said in an interview that the drug developers went through a “very rigorous process when selecting the guide RNA, which is what really targets the specificity of the TTR gene.”

“That’s a really, really important point,” he said. “When they did various studies using, for example, primary human hepatocytes, they found no evidence of off-target editing at concentrations of NTLA-2001 threefold greater than the EC90, the concentration at which one knocks down the protein by 90%. So, what we can say at the moment, is the specificity of NTLA-2001 for the TTR gene seems to be absolute.”

In terms of other challenges going forward, Dr. Gillmore added, “I think that it’s really to see whether the knockdown that is being achieved is going to translate into greater clinical benefit.”

Invited discussant Kevin M. Alexander, MD, of Stanford (Calif.) University, said therapies that stabilize or reduce TTR have recently emerged that have improved ATTR amyloidosis outcomes, including tafamidis and patisiran.

Nevertheless, there has been an unmet need to develop therapies that can halt or reverse disease, are effective in advanced ATTR, and have an improved route or frequency of administration, given that this is a chronic disease, he said.

Dr. Alexander noted that the reductions of greater than 90% were achieved with higher doses than used in the polyneuropathy arm reported last year but were well tolerated in patients that for the most part had wild-type ATTR (83%) and reflect the wild-type ATTR population in practice. “The data support consideration for subsequent efficacy trials for this compound.”

Unanswered questions in ongoing ATTR trials are whether TTR reductions translate into improved clinical outcomes, the long-term safety of TTR lowering, and the efficacy of NTLA-2001, particularly in higher-risk patients, such as those in NYHA class III and those with hereditary ATTR, Dr. Alexander said.

During a media briefing earlier in the day, invited discussant Kiran Musunuru, MD, University of Pennsylvania, Philadelphia, pointed out that, in the recent APOLLO-B trial of patisiran, patients with ATTR amyloidosis with cardiomyopathy had an average 87% TTR reduction but need intravenous infusions every 3 weeks for the rest of their lives.

“In contrast, gene editing is a one-and-done proposition,” he said. “You receive a single treatment that turns off the TTR gene permanently and the effects are durable and likely last a lifetime.”

Dr. Musunuru noted that patients who received patisiran also had significantly and substantially better functional capacity and quality of life, compared with those who received placebo. “Based on today’s results, we can expect future clinical trials for gene editing to have the same beneficial effects and possibly a mortality benefit as well.”

Today’s study is also important because it is part of the first wave of putting CRISPR into the body for an array of diseases, he commented.

“TTR gene editing stands out because it’s the very first CRISPR trial to show unequivocal success – you see that with a greater than 90% reduction in TTR,” Dr. Musunuru said. “So, in my view that makes it a milestone for modern medicine.”

Dosing at 55 mg, corresponding to a fixed 0.7 mg/kg dose, is ongoing in the dose-expansion portion of the trial, with enrollment across both arms expected to be completed by the end of 2022, Intellia Therapeutics reported.

The study was funded by Intellia Therapeutics and Regeneron Pharmaceuticals. Dr. Gillmore reports receiving consultancy fees from Alnylam, Ionis, AstraZeneca, Pfizer, Intellia, ATTRalus, and Novo Nordisk and has received grant support from Alnylam Pharmaceuticals. Dr. Alexander reports serving on advisory boards for Almylam and Arbor Biotechnologies; has consulted  for Eidos, Ionis, Novo Nordisk, and Pfizer; and has received grants from AHA, Alnylam, Eidos, and the National Institutes of Health.

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

CHICAGO – Treatment with the investigational CRISPR-Cas9 gene-editing therapy, NTLA-2001, led to rapid responses in patients with transthyretin (TTR) amyloidosis with cardiomyopathy (ATTR-CM), interim phase 1 results show.

Serum levels of the disease-causing TTR protein were reduced by at least 90% at day 28 with a single infusion of NTLA-2001 at two different doses, with reductions sustained across 4-6 months’ follow-up.

NTLA-2001 was generally well-tolerated, and the results were similar in patients with New York Heart Association (NYHA) class I-III heart failure.

“These data further support and extend the early findings demonstrating the promise of CRISPR-based in vivo genome editing in humans,” said Julian Gillmore, MD, PhD, MBBS, who is leading the study at University College London.

“More specifically, the deep TTR reductions observed in patients with ATTR amyloidosis in this study provide a real possibility of genuine clinical improvement in a condition that has hitherto been ultimately progressive and invariably fatal,” he said.

The results were reported in a late-breaking session at the American Heart Association scientific sessions.

Mutations in the TTR gene and age-related changes in the stability of the TTR protein can cause misfolding of the TTR protein, resulting in amyloid deposits in skin and myocardial tissues.

An estimated 50,000 people worldwide are thought to have hereditary ATTR and up to 500,000 to have wild-type ATTR amyloidosis. Amyloid cardiomyopathy is underdiagnosed and fatal in 3-10 years without treatment. Current treatment options only slow progression and require lifelong administration, he said.

Results reported last year from the polyneuropathy arm of the study were hailed as a breakthrough and further proof-of-concept that CRISPR could be used to treat other diseases

CRISPR gene editing has shown success, for example, in beta-thalassemia and sickle cell disease but involved stem cells extracted from patients’ bone marrow, edited in the lab, and then replaced.

NTLA-2001 (Intellia Therapeutics/Regeneron) is an in vivo treatment that uses lipid nanoparticles containing messenger RNA for Cas9 and a single-guide RNA targeting TTR in the liver, where it’s almost exclusively produced.

The new analysis included 12 patients with heart failure: 3 in NYHA  class I-II and 6 in NYHA class III who received a single dose of NTLA-2001 at 0.7 mg/kg, while the remaining 3 patients in NYHA class I-II received a single dose of 1.0 mg/kg.

During follow-up out to 6 months, TTR reductions averaged:

• 93% in the 0.7 mg/kg NYHA I-II group at 6 months.
• 94% in the 0.7 mg/kg NYHA III group at 4 months.
• 92% in the 1.0 mg/kg NYHA I-II group at 4 months.

Eight patients reported mild or moderate adverse events, and two patients experienced transient infusion reactions, including one grade 3 reaction in the 0.7 mg/kg NYHA class III group that resolved without clinical consequence. This group was expanded to six patients per study protocol. No additional treatment-related adverse events higher than grade 1 were reported, and no further dose escalation was undertaken, Dr. Gillmore reported.

There were no clinically relevant laboratory findings; one patient had a transient grade 1 liver enzyme elevation.

One disadvantage of CRISPR is the potential for off-target effects, but Dr. Gillmore said in an interview that the drug developers went through a “very rigorous process when selecting the guide RNA, which is what really targets the specificity of the TTR gene.”

“That’s a really, really important point,” he said. “When they did various studies using, for example, primary human hepatocytes, they found no evidence of off-target editing at concentrations of NTLA-2001 threefold greater than the EC90, the concentration at which one knocks down the protein by 90%. So, what we can say at the moment, is the specificity of NTLA-2001 for the TTR gene seems to be absolute.”

In terms of other challenges going forward, Dr. Gillmore added, “I think that it’s really to see whether the knockdown that is being achieved is going to translate into greater clinical benefit.”

Invited discussant Kevin M. Alexander, MD, of Stanford (Calif.) University, said therapies that stabilize or reduce TTR have recently emerged that have improved ATTR amyloidosis outcomes, including tafamidis and patisiran.

Nevertheless, there has been an unmet need to develop therapies that can halt or reverse disease, are effective in advanced ATTR, and have an improved route or frequency of administration, given that this is a chronic disease, he said.

Dr. Alexander noted that the reductions of greater than 90% were achieved with higher doses than used in the polyneuropathy arm reported last year but were well tolerated in patients that for the most part had wild-type ATTR (83%) and reflect the wild-type ATTR population in practice. “The data support consideration for subsequent efficacy trials for this compound.”

Unanswered questions in ongoing ATTR trials are whether TTR reductions translate into improved clinical outcomes, the long-term safety of TTR lowering, and the efficacy of NTLA-2001, particularly in higher-risk patients, such as those in NYHA class III and those with hereditary ATTR, Dr. Alexander said.

During a media briefing earlier in the day, invited discussant Kiran Musunuru, MD, University of Pennsylvania, Philadelphia, pointed out that, in the recent APOLLO-B trial of patisiran, patients with ATTR amyloidosis with cardiomyopathy had an average 87% TTR reduction but need intravenous infusions every 3 weeks for the rest of their lives.

“In contrast, gene editing is a one-and-done proposition,” he said. “You receive a single treatment that turns off the TTR gene permanently and the effects are durable and likely last a lifetime.”

Dr. Musunuru noted that patients who received patisiran also had significantly and substantially better functional capacity and quality of life, compared with those who received placebo. “Based on today’s results, we can expect future clinical trials for gene editing to have the same beneficial effects and possibly a mortality benefit as well.”

Today’s study is also important because it is part of the first wave of putting CRISPR into the body for an array of diseases, he commented.

“TTR gene editing stands out because it’s the very first CRISPR trial to show unequivocal success – you see that with a greater than 90% reduction in TTR,” Dr. Musunuru said. “So, in my view that makes it a milestone for modern medicine.”

Dosing at 55 mg, corresponding to a fixed 0.7 mg/kg dose, is ongoing in the dose-expansion portion of the trial, with enrollment across both arms expected to be completed by the end of 2022, Intellia Therapeutics reported.

The study was funded by Intellia Therapeutics and Regeneron Pharmaceuticals. Dr. Gillmore reports receiving consultancy fees from Alnylam, Ionis, AstraZeneca, Pfizer, Intellia, ATTRalus, and Novo Nordisk and has received grant support from Alnylam Pharmaceuticals. Dr. Alexander reports serving on advisory boards for Almylam and Arbor Biotechnologies; has consulted  for Eidos, Ionis, Novo Nordisk, and Pfizer; and has received grants from AHA, Alnylam, Eidos, and the National Institutes of Health.

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

CHICAGO – Treatment with the investigational CRISPR-Cas9 gene-editing therapy, NTLA-2001, led to rapid responses in patients with transthyretin (TTR) amyloidosis with cardiomyopathy (ATTR-CM), interim phase 1 results show.

Serum levels of the disease-causing TTR protein were reduced by at least 90% at day 28 with a single infusion of NTLA-2001 at two different doses, with reductions sustained across 4-6 months’ follow-up.

NTLA-2001 was generally well-tolerated, and the results were similar in patients with New York Heart Association (NYHA) class I-III heart failure.

“These data further support and extend the early findings demonstrating the promise of CRISPR-based in vivo genome editing in humans,” said Julian Gillmore, MD, PhD, MBBS, who is leading the study at University College London.

“More specifically, the deep TTR reductions observed in patients with ATTR amyloidosis in this study provide a real possibility of genuine clinical improvement in a condition that has hitherto been ultimately progressive and invariably fatal,” he said.

The results were reported in a late-breaking session at the American Heart Association scientific sessions.

Mutations in the TTR gene and age-related changes in the stability of the TTR protein can cause misfolding of the TTR protein, resulting in amyloid deposits in skin and myocardial tissues.

An estimated 50,000 people worldwide are thought to have hereditary ATTR and up to 500,000 to have wild-type ATTR amyloidosis. Amyloid cardiomyopathy is underdiagnosed and fatal in 3-10 years without treatment. Current treatment options only slow progression and require lifelong administration, he said.

Results reported last year from the polyneuropathy arm of the study were hailed as a breakthrough and further proof-of-concept that CRISPR could be used to treat other diseases

CRISPR gene editing has shown success, for example, in beta-thalassemia and sickle cell disease but involved stem cells extracted from patients’ bone marrow, edited in the lab, and then replaced.

NTLA-2001 (Intellia Therapeutics/Regeneron) is an in vivo treatment that uses lipid nanoparticles containing messenger RNA for Cas9 and a single-guide RNA targeting TTR in the liver, where it’s almost exclusively produced.

The new analysis included 12 patients with heart failure: 3 in NYHA  class I-II and 6 in NYHA class III who received a single dose of NTLA-2001 at 0.7 mg/kg, while the remaining 3 patients in NYHA class I-II received a single dose of 1.0 mg/kg.

During follow-up out to 6 months, TTR reductions averaged:

• 93% in the 0.7 mg/kg NYHA I-II group at 6 months.
• 94% in the 0.7 mg/kg NYHA III group at 4 months.
• 92% in the 1.0 mg/kg NYHA I-II group at 4 months.

Eight patients reported mild or moderate adverse events, and two patients experienced transient infusion reactions, including one grade 3 reaction in the 0.7 mg/kg NYHA class III group that resolved without clinical consequence. This group was expanded to six patients per study protocol. No additional treatment-related adverse events higher than grade 1 were reported, and no further dose escalation was undertaken, Dr. Gillmore reported.

There were no clinically relevant laboratory findings; one patient had a transient grade 1 liver enzyme elevation.

One disadvantage of CRISPR is the potential for off-target effects, but Dr. Gillmore said in an interview that the drug developers went through a “very rigorous process when selecting the guide RNA, which is what really targets the specificity of the TTR gene.”

“That’s a really, really important point,” he said. “When they did various studies using, for example, primary human hepatocytes, they found no evidence of off-target editing at concentrations of NTLA-2001 threefold greater than the EC90, the concentration at which one knocks down the protein by 90%. So, what we can say at the moment, is the specificity of NTLA-2001 for the TTR gene seems to be absolute.”

In terms of other challenges going forward, Dr. Gillmore added, “I think that it’s really to see whether the knockdown that is being achieved is going to translate into greater clinical benefit.”

Invited discussant Kevin M. Alexander, MD, of Stanford (Calif.) University, said therapies that stabilize or reduce TTR have recently emerged that have improved ATTR amyloidosis outcomes, including tafamidis and patisiran.

Nevertheless, there has been an unmet need to develop therapies that can halt or reverse disease, are effective in advanced ATTR, and have an improved route or frequency of administration, given that this is a chronic disease, he said.

Dr. Alexander noted that the reductions of greater than 90% were achieved with higher doses than used in the polyneuropathy arm reported last year but were well tolerated in patients that for the most part had wild-type ATTR (83%) and reflect the wild-type ATTR population in practice. “The data support consideration for subsequent efficacy trials for this compound.”

Unanswered questions in ongoing ATTR trials are whether TTR reductions translate into improved clinical outcomes, the long-term safety of TTR lowering, and the efficacy of NTLA-2001, particularly in higher-risk patients, such as those in NYHA class III and those with hereditary ATTR, Dr. Alexander said.

During a media briefing earlier in the day, invited discussant Kiran Musunuru, MD, University of Pennsylvania, Philadelphia, pointed out that, in the recent APOLLO-B trial of patisiran, patients with ATTR amyloidosis with cardiomyopathy had an average 87% TTR reduction but need intravenous infusions every 3 weeks for the rest of their lives.

“In contrast, gene editing is a one-and-done proposition,” he said. “You receive a single treatment that turns off the TTR gene permanently and the effects are durable and likely last a lifetime.”

Dr. Musunuru noted that patients who received patisiran also had significantly and substantially better functional capacity and quality of life, compared with those who received placebo. “Based on today’s results, we can expect future clinical trials for gene editing to have the same beneficial effects and possibly a mortality benefit as well.”

Today’s study is also important because it is part of the first wave of putting CRISPR into the body for an array of diseases, he commented.

“TTR gene editing stands out because it’s the very first CRISPR trial to show unequivocal success – you see that with a greater than 90% reduction in TTR,” Dr. Musunuru said. “So, in my view that makes it a milestone for modern medicine.”

Dosing at 55 mg, corresponding to a fixed 0.7 mg/kg dose, is ongoing in the dose-expansion portion of the trial, with enrollment across both arms expected to be completed by the end of 2022, Intellia Therapeutics reported.

The study was funded by Intellia Therapeutics and Regeneron Pharmaceuticals. Dr. Gillmore reports receiving consultancy fees from Alnylam, Ionis, AstraZeneca, Pfizer, Intellia, ATTRalus, and Novo Nordisk and has received grant support from Alnylam Pharmaceuticals. Dr. Alexander reports serving on advisory boards for Almylam and Arbor Biotechnologies; has consulted  for Eidos, Ionis, Novo Nordisk, and Pfizer; and has received grants from AHA, Alnylam, Eidos, and the National Institutes of Health.

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

CHICAGO – The choice of loop diuretic for decongestion in patients hospitalized with heart failure (HF) may make little difference to survival or readmission risk over the next year, at least when deciding between furosemide or torsemide, a randomized trial suggests.

Both drugs are old and widely used, but differences between the two loop diuretics in bioavailability, effects on potassium levels, and other features have led some clinicians to sometimes prefer torsemide. Until now, however, no randomized HF trials have compared the two drugs.

The new findings suggest clinicians can continue starting such patients with HF on either agent, at their discretion, without concern that the choice may compromise outcomes, say researchers from the TRANSFORM-HF trial, which compared furosemide-first and torsemide-first diuretic strategies in a diverse population of patients with HF.

Given that the two strategies were similarly effective for survival and rehospitalization, clinicians caring for patients with HF can focus more on “getting patients on the right dose for their loop diuretic, and prioritizing those therapies proven to improve clinical outcomes,” said Robert J. Mentz, MD, of Duke University Clinical Research Institute, Durham, N.C.

Dr. Mentz, a TRANSFORM-HF principal investigator, presented the primary results November 5 at the American Heart Association scientific sessions.

The trial had randomly assigned 2,859 patients hospitalized with HF and with a plan for oral loop diuretic therapy to initiate treatment with furosemide or torsemide. Clinicians were encouraged to maintain patients on the assigned diuretic, but crossovers to the other drug or other diuretic changes were allowed.

Rates of death from any cause, the primary endpoint, were about 26% in both groups over a median 17-month follow-up, regardless of ejection fraction (EF).

The composite rates of all-cause death or hospitalization at 12 months were also not significantly different, about 49% for those started on furosemide and about 47% for patients initially prescribed torsemide.

As a pragmatic comparative effectiveness trial, TRANSFORM-HF entered diverse patients with HF, broadly representative of actual clinical practice, who were managed according to routine practice and a streamlined study protocol at more than 60 U.S. centers, Dr. Mentz observed.

One of the pragmatic design’s advantages, he told this news organization, was “how efficient it was” as a randomized comparison of treatment strategies for clinical outcomes. It was “relatively low cost” and recruited patients quickly, compared with conventional randomized trials, “and we answered the question clearly.” The trial’s results, Dr. Mentz said, reflect “what happens in the real world.”

When might torsemide have the edge?

Although furosemide is the most commonly used loop diuretic in HF, and there are others besides it and torsemide, the latter has both known and theoretical advantages that set it apart. Torsemide is more than twice as potent as furosemide and more bioavailable, and its treatment effect lasts longer, the TRANSFORM-HF investigators have noted.

In addition, preclinical and small clinical studies suggest torsemide may have pleiotropic effects that might be theoretical advantages for patients with HF. For example, it appears to downregulate the renin-angiotensin-aldosterone system (RAAS) and reduce myocardial fibrosis and promote reverse ventricular remodeling, the group writes.

In practice, therefore, torsemide may be preferred in patients with furosemide resistance or “challenges with bioavailability, especially those with very advanced heart failure with congestion who may have gut edema, where oral furosemide and other loop diuretics are not effectively absorbed,” Biykem Bozkurt, MD, PhD, Baylor College of Medicine, Houston, told this news organization.  

In such patients, she said, torsemide “is considered to be a better choice  for individuals who have diuretic resistance with advanced congestion.”

The drug’s apparent pleiotropic effects, such as RAAS inhibition, may have less relevance to the TRANSFORM-HF primary endpoint of all-cause mortality than to clinical outcomes more likely associated with successful decongestion, such as HF hospitalization, Dr. Bozkurt proposed.

The trial’s pragmatic design, however, made it more feasible to focus on all-cause mortality and less practical to use measures of successful decongestion, such as volume loss or reduction in natriuretic peptide levels, she observed. Those are endpoints of special interest when diuretics are compared, “especially for the subgroup of patients who are diuretic resistant.”

Over the last 20 years or so, “we’ve learned that hospitalized heart failure is a very different disease process with a different natural history,” observed Clyde W. Yancy, MD, MSc, Northwestern University, Chicago, who was not part of the current study.

“So, the idea that something as nuanced as choice of one loop diuretic over the other, in that setting, would be sufficient to change the natural history, may be still a high bar for us,” he said in an interview.

“Based on these data, one would have to argue that whichever loop diuretic you select for the hospitalized patient – and a lot of that is driven by market exigencies right now – it turns out that the response is indistinguishable,” Dr. Yancy said. “That means  if your hospital happens to have furosemide on the formulary, use it. If furosemide is not available but torsemide is available, use it.”

Dr. Yancy said he’d like to see a trial similar to TRANSFORM-HF but in outpatients receiving today’s guideline-directed medical therapy, which includes the sodium-glucose cotransporter 2 (SGLT2) inhibitors, drugs that increase the fractional excretion of sodium and have a “diureticlike” effect.

Such a trial, he said, would explore “the combination of not one, or two, but three agents with a diuretic effect – a loop diuretic, a mineralocorticoid antagonist, and an SGLT2 inhibitor – in ambulatory, optimized patients. It might make a difference.”

HF regardless of EF

The trial enrolled patients hospitalized with worsening or new-onset HF with a plan for long-term loop diuretic therapy who had either an EF of 40% or lower or, regardless of EF, elevated natriuretic peptide levels when hospitalized.

Of the 2,859 participants, whose mean age was about 65 years, about 36% were women and 34% African American. Overall, 1,428 were assigned to receive furosemide as their initial oral diuretic and 1,431 patients were assigned to the torsemide-first strategy.

The rate of death from any cause in both groups was 17 per 100 patient-years at a median of 17.4 months. The hazard ratio for torsemide vs. furosemide was 1.02 (95% confidence interval, 0.89-1.18; P = .77).

The corresponding HR at 12 months for all-cause death or hospitalization was 0.92 (95% CI, 0.83-1.02;  P = .11). The relative risk for any hospitalization was 0.94 (95% CI, 0.84-1.07).

Pragmatic design: Other implications

Dosing was left to clinician discretion in the open-label study, as was whether patients maintained their assigned drug or switched over to the other agent. Indeed, 5.4% of patients crossed over to the other loop diuretic, and 2.8% went off loop diuretics entirely between in-hospital randomization and discharge, Dr. Mentz reported. By day 30, 6.7% had crossed over, and 7% had stopped taking loop diuretics.

The diuretic crossovers and discontinuations, Dr. Mentz said, likely biased the trial’s outcomes, such that the two strategies performed about equally well. Efforts were made, however, to at least partially overcome that limitation.

“We put measures in place to support adherence – sending letters to their primary doctors, giving them a wallet card so they would know which therapy they were on, having conversations about the importance of trying to stay on the randomized therapy,” Dr. Mentz said in an interview. Still, some clinicians saw differences between the two agents that prompted them, at some point, to switch patients from one loop diuretic to the other.

But interestingly, Dr. Mentz reported, the two strategies did not significantly differ in all-cause mortality or the composite of all-cause mortality or hospitalization in analysis by intention to treat.

Dr. Mentz discloses receiving honoraria from AstraZeneca, Bayer/Merck, Boehringer Ingelheim/Lilly, Cytokinetics, Pharmacosmos, Respicardia, Windtree Therapeutics, and Zoll; and research grants from American Regent and Novartis. Dr. Bozkurt discloses receiving honoraria from AstraZeneca, Baxter Health Care, and Sanofi Aventis and having other relationships with Renovacor, Respicardia, Abbott Vascular, Liva Nova, Vifor, and Cardurion. Dr. Yancy discloses a modest relationship with Abbott.

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

CHICAGO – The choice of loop diuretic for decongestion in patients hospitalized with heart failure (HF) may make little difference to survival or readmission risk over the next year, at least when deciding between furosemide or torsemide, a randomized trial suggests.

Both drugs are old and widely used, but differences between the two loop diuretics in bioavailability, effects on potassium levels, and other features have led some clinicians to sometimes prefer torsemide. Until now, however, no randomized HF trials have compared the two drugs.

The new findings suggest clinicians can continue starting such patients with HF on either agent, at their discretion, without concern that the choice may compromise outcomes, say researchers from the TRANSFORM-HF trial, which compared furosemide-first and torsemide-first diuretic strategies in a diverse population of patients with HF.

Given that the two strategies were similarly effective for survival and rehospitalization, clinicians caring for patients with HF can focus more on “getting patients on the right dose for their loop diuretic, and prioritizing those therapies proven to improve clinical outcomes,” said Robert J. Mentz, MD, of Duke University Clinical Research Institute, Durham, N.C.

Dr. Mentz, a TRANSFORM-HF principal investigator, presented the primary results November 5 at the American Heart Association scientific sessions.

The trial had randomly assigned 2,859 patients hospitalized with HF and with a plan for oral loop diuretic therapy to initiate treatment with furosemide or torsemide. Clinicians were encouraged to maintain patients on the assigned diuretic, but crossovers to the other drug or other diuretic changes were allowed.

Rates of death from any cause, the primary endpoint, were about 26% in both groups over a median 17-month follow-up, regardless of ejection fraction (EF).

The composite rates of all-cause death or hospitalization at 12 months were also not significantly different, about 49% for those started on furosemide and about 47% for patients initially prescribed torsemide.

As a pragmatic comparative effectiveness trial, TRANSFORM-HF entered diverse patients with HF, broadly representative of actual clinical practice, who were managed according to routine practice and a streamlined study protocol at more than 60 U.S. centers, Dr. Mentz observed.

One of the pragmatic design’s advantages, he told this news organization, was “how efficient it was” as a randomized comparison of treatment strategies for clinical outcomes. It was “relatively low cost” and recruited patients quickly, compared with conventional randomized trials, “and we answered the question clearly.” The trial’s results, Dr. Mentz said, reflect “what happens in the real world.”

When might torsemide have the edge?

Although furosemide is the most commonly used loop diuretic in HF, and there are others besides it and torsemide, the latter has both known and theoretical advantages that set it apart. Torsemide is more than twice as potent as furosemide and more bioavailable, and its treatment effect lasts longer, the TRANSFORM-HF investigators have noted.

In addition, preclinical and small clinical studies suggest torsemide may have pleiotropic effects that might be theoretical advantages for patients with HF. For example, it appears to downregulate the renin-angiotensin-aldosterone system (RAAS) and reduce myocardial fibrosis and promote reverse ventricular remodeling, the group writes.

In practice, therefore, torsemide may be preferred in patients with furosemide resistance or “challenges with bioavailability, especially those with very advanced heart failure with congestion who may have gut edema, where oral furosemide and other loop diuretics are not effectively absorbed,” Biykem Bozkurt, MD, PhD, Baylor College of Medicine, Houston, told this news organization.  

In such patients, she said, torsemide “is considered to be a better choice  for individuals who have diuretic resistance with advanced congestion.”

The drug’s apparent pleiotropic effects, such as RAAS inhibition, may have less relevance to the TRANSFORM-HF primary endpoint of all-cause mortality than to clinical outcomes more likely associated with successful decongestion, such as HF hospitalization, Dr. Bozkurt proposed.

The trial’s pragmatic design, however, made it more feasible to focus on all-cause mortality and less practical to use measures of successful decongestion, such as volume loss or reduction in natriuretic peptide levels, she observed. Those are endpoints of special interest when diuretics are compared, “especially for the subgroup of patients who are diuretic resistant.”

Over the last 20 years or so, “we’ve learned that hospitalized heart failure is a very different disease process with a different natural history,” observed Clyde W. Yancy, MD, MSc, Northwestern University, Chicago, who was not part of the current study.

“So, the idea that something as nuanced as choice of one loop diuretic over the other, in that setting, would be sufficient to change the natural history, may be still a high bar for us,” he said in an interview.

“Based on these data, one would have to argue that whichever loop diuretic you select for the hospitalized patient – and a lot of that is driven by market exigencies right now – it turns out that the response is indistinguishable,” Dr. Yancy said. “That means  if your hospital happens to have furosemide on the formulary, use it. If furosemide is not available but torsemide is available, use it.”

Dr. Yancy said he’d like to see a trial similar to TRANSFORM-HF but in outpatients receiving today’s guideline-directed medical therapy, which includes the sodium-glucose cotransporter 2 (SGLT2) inhibitors, drugs that increase the fractional excretion of sodium and have a “diureticlike” effect.

Such a trial, he said, would explore “the combination of not one, or two, but three agents with a diuretic effect – a loop diuretic, a mineralocorticoid antagonist, and an SGLT2 inhibitor – in ambulatory, optimized patients. It might make a difference.”

HF regardless of EF

The trial enrolled patients hospitalized with worsening or new-onset HF with a plan for long-term loop diuretic therapy who had either an EF of 40% or lower or, regardless of EF, elevated natriuretic peptide levels when hospitalized.

Of the 2,859 participants, whose mean age was about 65 years, about 36% were women and 34% African American. Overall, 1,428 were assigned to receive furosemide as their initial oral diuretic and 1,431 patients were assigned to the torsemide-first strategy.

The rate of death from any cause in both groups was 17 per 100 patient-years at a median of 17.4 months. The hazard ratio for torsemide vs. furosemide was 1.02 (95% confidence interval, 0.89-1.18; P = .77).

The corresponding HR at 12 months for all-cause death or hospitalization was 0.92 (95% CI, 0.83-1.02;  P = .11). The relative risk for any hospitalization was 0.94 (95% CI, 0.84-1.07).

Pragmatic design: Other implications

Dosing was left to clinician discretion in the open-label study, as was whether patients maintained their assigned drug or switched over to the other agent. Indeed, 5.4% of patients crossed over to the other loop diuretic, and 2.8% went off loop diuretics entirely between in-hospital randomization and discharge, Dr. Mentz reported. By day 30, 6.7% had crossed over, and 7% had stopped taking loop diuretics.

The diuretic crossovers and discontinuations, Dr. Mentz said, likely biased the trial’s outcomes, such that the two strategies performed about equally well. Efforts were made, however, to at least partially overcome that limitation.

“We put measures in place to support adherence – sending letters to their primary doctors, giving them a wallet card so they would know which therapy they were on, having conversations about the importance of trying to stay on the randomized therapy,” Dr. Mentz said in an interview. Still, some clinicians saw differences between the two agents that prompted them, at some point, to switch patients from one loop diuretic to the other.

But interestingly, Dr. Mentz reported, the two strategies did not significantly differ in all-cause mortality or the composite of all-cause mortality or hospitalization in analysis by intention to treat.

Dr. Mentz discloses receiving honoraria from AstraZeneca, Bayer/Merck, Boehringer Ingelheim/Lilly, Cytokinetics, Pharmacosmos, Respicardia, Windtree Therapeutics, and Zoll; and research grants from American Regent and Novartis. Dr. Bozkurt discloses receiving honoraria from AstraZeneca, Baxter Health Care, and Sanofi Aventis and having other relationships with Renovacor, Respicardia, Abbott Vascular, Liva Nova, Vifor, and Cardurion. Dr. Yancy discloses a modest relationship with Abbott.

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

CHICAGO – The choice of loop diuretic for decongestion in patients hospitalized with heart failure (HF) may make little difference to survival or readmission risk over the next year, at least when deciding between furosemide or torsemide, a randomized trial suggests.

Both drugs are old and widely used, but differences between the two loop diuretics in bioavailability, effects on potassium levels, and other features have led some clinicians to sometimes prefer torsemide. Until now, however, no randomized HF trials have compared the two drugs.

The new findings suggest clinicians can continue starting such patients with HF on either agent, at their discretion, without concern that the choice may compromise outcomes, say researchers from the TRANSFORM-HF trial, which compared furosemide-first and torsemide-first diuretic strategies in a diverse population of patients with HF.

Given that the two strategies were similarly effective for survival and rehospitalization, clinicians caring for patients with HF can focus more on “getting patients on the right dose for their loop diuretic, and prioritizing those therapies proven to improve clinical outcomes,” said Robert J. Mentz, MD, of Duke University Clinical Research Institute, Durham, N.C.

Dr. Mentz, a TRANSFORM-HF principal investigator, presented the primary results November 5 at the American Heart Association scientific sessions.

The trial had randomly assigned 2,859 patients hospitalized with HF and with a plan for oral loop diuretic therapy to initiate treatment with furosemide or torsemide. Clinicians were encouraged to maintain patients on the assigned diuretic, but crossovers to the other drug or other diuretic changes were allowed.

Rates of death from any cause, the primary endpoint, were about 26% in both groups over a median 17-month follow-up, regardless of ejection fraction (EF).

The composite rates of all-cause death or hospitalization at 12 months were also not significantly different, about 49% for those started on furosemide and about 47% for patients initially prescribed torsemide.

As a pragmatic comparative effectiveness trial, TRANSFORM-HF entered diverse patients with HF, broadly representative of actual clinical practice, who were managed according to routine practice and a streamlined study protocol at more than 60 U.S. centers, Dr. Mentz observed.

One of the pragmatic design’s advantages, he told this news organization, was “how efficient it was” as a randomized comparison of treatment strategies for clinical outcomes. It was “relatively low cost” and recruited patients quickly, compared with conventional randomized trials, “and we answered the question clearly.” The trial’s results, Dr. Mentz said, reflect “what happens in the real world.”

When might torsemide have the edge?

Although furosemide is the most commonly used loop diuretic in HF, and there are others besides it and torsemide, the latter has both known and theoretical advantages that set it apart. Torsemide is more than twice as potent as furosemide and more bioavailable, and its treatment effect lasts longer, the TRANSFORM-HF investigators have noted.

In addition, preclinical and small clinical studies suggest torsemide may have pleiotropic effects that might be theoretical advantages for patients with HF. For example, it appears to downregulate the renin-angiotensin-aldosterone system (RAAS) and reduce myocardial fibrosis and promote reverse ventricular remodeling, the group writes.

In practice, therefore, torsemide may be preferred in patients with furosemide resistance or “challenges with bioavailability, especially those with very advanced heart failure with congestion who may have gut edema, where oral furosemide and other loop diuretics are not effectively absorbed,” Biykem Bozkurt, MD, PhD, Baylor College of Medicine, Houston, told this news organization.  

In such patients, she said, torsemide “is considered to be a better choice  for individuals who have diuretic resistance with advanced congestion.”

The drug’s apparent pleiotropic effects, such as RAAS inhibition, may have less relevance to the TRANSFORM-HF primary endpoint of all-cause mortality than to clinical outcomes more likely associated with successful decongestion, such as HF hospitalization, Dr. Bozkurt proposed.

The trial’s pragmatic design, however, made it more feasible to focus on all-cause mortality and less practical to use measures of successful decongestion, such as volume loss or reduction in natriuretic peptide levels, she observed. Those are endpoints of special interest when diuretics are compared, “especially for the subgroup of patients who are diuretic resistant.”

Over the last 20 years or so, “we’ve learned that hospitalized heart failure is a very different disease process with a different natural history,” observed Clyde W. Yancy, MD, MSc, Northwestern University, Chicago, who was not part of the current study.

“So, the idea that something as nuanced as choice of one loop diuretic over the other, in that setting, would be sufficient to change the natural history, may be still a high bar for us,” he said in an interview.

“Based on these data, one would have to argue that whichever loop diuretic you select for the hospitalized patient – and a lot of that is driven by market exigencies right now – it turns out that the response is indistinguishable,” Dr. Yancy said. “That means  if your hospital happens to have furosemide on the formulary, use it. If furosemide is not available but torsemide is available, use it.”

Dr. Yancy said he’d like to see a trial similar to TRANSFORM-HF but in outpatients receiving today’s guideline-directed medical therapy, which includes the sodium-glucose cotransporter 2 (SGLT2) inhibitors, drugs that increase the fractional excretion of sodium and have a “diureticlike” effect.

Such a trial, he said, would explore “the combination of not one, or two, but three agents with a diuretic effect – a loop diuretic, a mineralocorticoid antagonist, and an SGLT2 inhibitor – in ambulatory, optimized patients. It might make a difference.”

HF regardless of EF

The trial enrolled patients hospitalized with worsening or new-onset HF with a plan for long-term loop diuretic therapy who had either an EF of 40% or lower or, regardless of EF, elevated natriuretic peptide levels when hospitalized.

Of the 2,859 participants, whose mean age was about 65 years, about 36% were women and 34% African American. Overall, 1,428 were assigned to receive furosemide as their initial oral diuretic and 1,431 patients were assigned to the torsemide-first strategy.

The rate of death from any cause in both groups was 17 per 100 patient-years at a median of 17.4 months. The hazard ratio for torsemide vs. furosemide was 1.02 (95% confidence interval, 0.89-1.18; P = .77).

The corresponding HR at 12 months for all-cause death or hospitalization was 0.92 (95% CI, 0.83-1.02;  P = .11). The relative risk for any hospitalization was 0.94 (95% CI, 0.84-1.07).

Pragmatic design: Other implications

Dosing was left to clinician discretion in the open-label study, as was whether patients maintained their assigned drug or switched over to the other agent. Indeed, 5.4% of patients crossed over to the other loop diuretic, and 2.8% went off loop diuretics entirely between in-hospital randomization and discharge, Dr. Mentz reported. By day 30, 6.7% had crossed over, and 7% had stopped taking loop diuretics.

The diuretic crossovers and discontinuations, Dr. Mentz said, likely biased the trial’s outcomes, such that the two strategies performed about equally well. Efforts were made, however, to at least partially overcome that limitation.

“We put measures in place to support adherence – sending letters to their primary doctors, giving them a wallet card so they would know which therapy they were on, having conversations about the importance of trying to stay on the randomized therapy,” Dr. Mentz said in an interview. Still, some clinicians saw differences between the two agents that prompted them, at some point, to switch patients from one loop diuretic to the other.

But interestingly, Dr. Mentz reported, the two strategies did not significantly differ in all-cause mortality or the composite of all-cause mortality or hospitalization in analysis by intention to treat.

Dr. Mentz discloses receiving honoraria from AstraZeneca, Bayer/Merck, Boehringer Ingelheim/Lilly, Cytokinetics, Pharmacosmos, Respicardia, Windtree Therapeutics, and Zoll; and research grants from American Regent and Novartis. Dr. Bozkurt discloses receiving honoraria from AstraZeneca, Baxter Health Care, and Sanofi Aventis and having other relationships with Renovacor, Respicardia, Abbott Vascular, Liva Nova, Vifor, and Cardurion. Dr. Yancy discloses a modest relationship with Abbott.

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

There was no difference in major cardiovascular outcomes with the use of two different diuretics – chlorthalidone or hydrochlorothiazide – in the treatment of hypertension in a new large randomized real-world study.

The Diuretic Comparison Project (DCP), which was conducted in more than 13,500 U.S. veterans age 65 years or over, showed almost identical rates of the primary composite endpoint, including myocardial infarction (MI), stroke, noncancer death, hospitalization for acute heart failure, or urgent revascularization, after a median of 2.4 years of follow-up.

There was no difference in any of the individual endpoints or other secondary cardiovascular outcomes.

However, in the subgroup of patients who had a history of MI or stroke (who made up about 10% of the study population), there was a significant reduction in the primary endpoint with chlorthalidone, whereas those without a history of MI or stroke appeared to have an increased risk for primary outcome events while receiving chlorthalidone compared with those receiving hydrochlorothiazide.

The DCP trial was presented at the American Heart Association scientific sessions by Areef Ishani, MD, director of the Minneapolis Primary Care and Specialty Care Integrated Care Community and director of the Veterans Affairs (VA) Midwest Health Care Network.

Asked how to interpret the result for clinical practice, Dr. Ishani said, “I think we can now say that either of these two drugs is appropriate to use for the treatment of hypertension.”

But he added that the decision on what to do with the subgroup of patients with previous MI or stroke was more “challenging.”

“We saw a highly significant benefit in this subgroup, but this was in the context of an overall negative trial,” he noted. “I think this is a discussion with the patients on how they want to hedge their bets. Because these two drugs are so similar, if they wanted to take one or the other because of this subgroup result I think that is a conversation to have, but I think we now need to conduct another trial specifically in this subgroup of patients to see if chlorthalidone really is of benefit in that group.”

Dr. Ishani explained that both chlorthalidone and hydrochlorothiazide have been around for more than 50 years and are considered first-line treatments for hypertension. Early studies suggested better cardiovascular outcomes and 24-hour blood pressure control with chlorthalidone, but recent observational studies have not shown more benefit with chlorthalidone. These studies have suggested that chlorthalidone may be associated with an increase in adverse events, such as hypokalemia, acute kidney injury, and chronic kidney disease.
 

Pragmatic study

The DCP trial was conducted to try to definitively answer this question of whether chlorthalidone is superior to hydrochlorothiazide. The pragmatic study had a “point-of-care” design that allowed participants and health care professionals to know which medication was being prescribed and to administer the medication in a real-world setting.

“Patients can continue with their normal care with their usual care team because we integrated this trial into primary care clinics,” Dr. Ishani said. “We followed participant results using their electronic health record. This study was nonintrusive, cost-effective, and inexpensive. Plus, we were able to recruit a large rural population, which is unusual for large, randomized trials, where we usually rely on big academic medical centers.”

Using VA electronic medical records, the investigators recruited primary care physicians who identified patients older than age 65 years who were receiving hydrochlorothiazide (25 mg or 50 mg) for hypertension. These patients (97% of whom were male) were then randomly assigned to continue receiving hydrochlorothiazide or to switch to an equivalent dose of chlorthalidone. Patients were followed through the electronic medical record as well as Medicare claims and the National Death Index.

Results after a median follow-up of 2.4 years showed no difference in blood pressure control between the two groups.

In terms of clinical events, the primary composite outcome of MI, stroke, noncancer death, hospitalization for acute heart failure, or urgent revascularization occurred in 10.4% of the chlorthalidone group and in 10.0% of the hydrochlorothiazide group (hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.94-1.16; P = .4).

There was no difference in any individual components of the primary endpoint or the secondary outcomes of all-cause mortality, any revascularization, or erectile dysfunction.

In terms of adverse events, chlorthalidone was associated with an increase in hypokalemia (6% vs. 4.4%; HR, 1.38), but there was no difference in hospitalization for acute kidney injury.
 

Benefit in MI, stroke subgroup?

In the subgroup analysis, patients with a history of MI or stroke who were receiving chlorthalidone had a significant 27% reduction in the primary endpoint (HR, 0.73; 95% CI, 0.57-0.94). Conversely, patients without a history of MI or stroke appeared to do worse while taking chlorthalidone (HR, 1.12; 95% CI, 1.00-1.26).

“We were surprised by these results,” Dr. Ishani said. “We expected chlorthalidone to be more effective overall. However, learning about these differences in patients who have a history of cardiovascular disease may affect patient care. It’s best for people to talk with their health care clinicians about which of these medications is better for their individual needs.”

He added: “More research is needed to explore these results further because we don’t know how they may fit into treating the general population.”

Dr. Ishani noted that a limitations of this study was that most patients were receiving the low dose of chlorthalidone, and previous studies that suggested benefits with chlorthalidone used the higher dose.

“But the world has voted – we had 4,000 clinicians involved in this study, and the vast majority are using the low dose of hydrochlorothiazide. And this is a definitively negative study,” he said. “The world has also voted in that 10 times more patients were on hydrochlorothiazide than on chlorthalidone.”

Commenting on the study at an AHA press conference, Biykem Bozkurt, MD, PhD, Baylor College of Medicine, Houston, pointed out that in all of the landmark National Institutes of Health hypertension trials, there was a signal for benefit with chlorthalidone compared with other antihypertensives.

Catherine Hackett/MDedge News

“We’ve always had this concept that chlorthalidone is better,” she said. “But this study shows no difference in major cardiovascular endpoints. There was more hypokalemia with chlorthalidone, but that’s recognizable as chlorthalidone is a more potent diuretic.”

Other limitations of the DCP trial are its open-label design, which could interject some bias; the enduring effects of hydrochlorothiazide – most of these patients were receiving this agent as background therapy; and inability to look at the effectiveness of decongestion of the agents in such a pragmatic study, Dr. Bozkurt noted.

She said she would like to see more analysis in the subgroup of patients with previous MI or stroke. “Does this result mean that chlorthalidone is better for sicker patients or is this result just due to chance?” she asked.

“While this study demonstrates equal effectiveness of these two diuretics in the targeted population, the question of subgroups of patients for which we use a more potent diuretic I think remains unanswered,” she concluded.

Designated discussant of the DCP trial at the late-breaking trial session, Daniel Levy, MD, director of the Framingham Heart Study at the National Heart, Lung, and Blood Institute, reminded attendees that chlorthalidone had shown impressive results in previous important hypertension studies including SHEP and ALLHAT.

He said the current DCP was a pragmatic study addressing a knowledge gap that “would never have been performed by industry.”

Dr. Levy concluded that the results showing no difference in outcomes between the two diuretics were “compelling,” although a few questions remain.

These include a possible bias toward hydrochlorothiazide – patients were selected who were already taking that drug and so would have already had a favorable response to it. In addition, because the trial was conducted in an older male population, he questioned whether the results could be generalized to women and younger patients.

The DCP study was funded by the VA Cooperative Studies Program. Dr. Ishani reported no disclosures.

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

There was no difference in major cardiovascular outcomes with the use of two different diuretics – chlorthalidone or hydrochlorothiazide – in the treatment of hypertension in a new large randomized real-world study.

The Diuretic Comparison Project (DCP), which was conducted in more than 13,500 U.S. veterans age 65 years or over, showed almost identical rates of the primary composite endpoint, including myocardial infarction (MI), stroke, noncancer death, hospitalization for acute heart failure, or urgent revascularization, after a median of 2.4 years of follow-up.

There was no difference in any of the individual endpoints or other secondary cardiovascular outcomes.

However, in the subgroup of patients who had a history of MI or stroke (who made up about 10% of the study population), there was a significant reduction in the primary endpoint with chlorthalidone, whereas those without a history of MI or stroke appeared to have an increased risk for primary outcome events while receiving chlorthalidone compared with those receiving hydrochlorothiazide.

The DCP trial was presented at the American Heart Association scientific sessions by Areef Ishani, MD, director of the Minneapolis Primary Care and Specialty Care Integrated Care Community and director of the Veterans Affairs (VA) Midwest Health Care Network.

Asked how to interpret the result for clinical practice, Dr. Ishani said, “I think we can now say that either of these two drugs is appropriate to use for the treatment of hypertension.”

But he added that the decision on what to do with the subgroup of patients with previous MI or stroke was more “challenging.”

“We saw a highly significant benefit in this subgroup, but this was in the context of an overall negative trial,” he noted. “I think this is a discussion with the patients on how they want to hedge their bets. Because these two drugs are so similar, if they wanted to take one or the other because of this subgroup result I think that is a conversation to have, but I think we now need to conduct another trial specifically in this subgroup of patients to see if chlorthalidone really is of benefit in that group.”

Dr. Ishani explained that both chlorthalidone and hydrochlorothiazide have been around for more than 50 years and are considered first-line treatments for hypertension. Early studies suggested better cardiovascular outcomes and 24-hour blood pressure control with chlorthalidone, but recent observational studies have not shown more benefit with chlorthalidone. These studies have suggested that chlorthalidone may be associated with an increase in adverse events, such as hypokalemia, acute kidney injury, and chronic kidney disease.
 

Pragmatic study

The DCP trial was conducted to try to definitively answer this question of whether chlorthalidone is superior to hydrochlorothiazide. The pragmatic study had a “point-of-care” design that allowed participants and health care professionals to know which medication was being prescribed and to administer the medication in a real-world setting.

“Patients can continue with their normal care with their usual care team because we integrated this trial into primary care clinics,” Dr. Ishani said. “We followed participant results using their electronic health record. This study was nonintrusive, cost-effective, and inexpensive. Plus, we were able to recruit a large rural population, which is unusual for large, randomized trials, where we usually rely on big academic medical centers.”

Using VA electronic medical records, the investigators recruited primary care physicians who identified patients older than age 65 years who were receiving hydrochlorothiazide (25 mg or 50 mg) for hypertension. These patients (97% of whom were male) were then randomly assigned to continue receiving hydrochlorothiazide or to switch to an equivalent dose of chlorthalidone. Patients were followed through the electronic medical record as well as Medicare claims and the National Death Index.

Results after a median follow-up of 2.4 years showed no difference in blood pressure control between the two groups.

In terms of clinical events, the primary composite outcome of MI, stroke, noncancer death, hospitalization for acute heart failure, or urgent revascularization occurred in 10.4% of the chlorthalidone group and in 10.0% of the hydrochlorothiazide group (hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.94-1.16; P = .4).

There was no difference in any individual components of the primary endpoint or the secondary outcomes of all-cause mortality, any revascularization, or erectile dysfunction.

In terms of adverse events, chlorthalidone was associated with an increase in hypokalemia (6% vs. 4.4%; HR, 1.38), but there was no difference in hospitalization for acute kidney injury.
 

Benefit in MI, stroke subgroup?

In the subgroup analysis, patients with a history of MI or stroke who were receiving chlorthalidone had a significant 27% reduction in the primary endpoint (HR, 0.73; 95% CI, 0.57-0.94). Conversely, patients without a history of MI or stroke appeared to do worse while taking chlorthalidone (HR, 1.12; 95% CI, 1.00-1.26).

“We were surprised by these results,” Dr. Ishani said. “We expected chlorthalidone to be more effective overall. However, learning about these differences in patients who have a history of cardiovascular disease may affect patient care. It’s best for people to talk with their health care clinicians about which of these medications is better for their individual needs.”

He added: “More research is needed to explore these results further because we don’t know how they may fit into treating the general population.”

Dr. Ishani noted that a limitations of this study was that most patients were receiving the low dose of chlorthalidone, and previous studies that suggested benefits with chlorthalidone used the higher dose.

“But the world has voted – we had 4,000 clinicians involved in this study, and the vast majority are using the low dose of hydrochlorothiazide. And this is a definitively negative study,” he said. “The world has also voted in that 10 times more patients were on hydrochlorothiazide than on chlorthalidone.”

Commenting on the study at an AHA press conference, Biykem Bozkurt, MD, PhD, Baylor College of Medicine, Houston, pointed out that in all of the landmark National Institutes of Health hypertension trials, there was a signal for benefit with chlorthalidone compared with other antihypertensives.

Catherine Hackett/MDedge News

“We’ve always had this concept that chlorthalidone is better,” she said. “But this study shows no difference in major cardiovascular endpoints. There was more hypokalemia with chlorthalidone, but that’s recognizable as chlorthalidone is a more potent diuretic.”

Other limitations of the DCP trial are its open-label design, which could interject some bias; the enduring effects of hydrochlorothiazide – most of these patients were receiving this agent as background therapy; and inability to look at the effectiveness of decongestion of the agents in such a pragmatic study, Dr. Bozkurt noted.

She said she would like to see more analysis in the subgroup of patients with previous MI or stroke. “Does this result mean that chlorthalidone is better for sicker patients or is this result just due to chance?” she asked.

“While this study demonstrates equal effectiveness of these two diuretics in the targeted population, the question of subgroups of patients for which we use a more potent diuretic I think remains unanswered,” she concluded.

Designated discussant of the DCP trial at the late-breaking trial session, Daniel Levy, MD, director of the Framingham Heart Study at the National Heart, Lung, and Blood Institute, reminded attendees that chlorthalidone had shown impressive results in previous important hypertension studies including SHEP and ALLHAT.

He said the current DCP was a pragmatic study addressing a knowledge gap that “would never have been performed by industry.”

Dr. Levy concluded that the results showing no difference in outcomes between the two diuretics were “compelling,” although a few questions remain.

These include a possible bias toward hydrochlorothiazide – patients were selected who were already taking that drug and so would have already had a favorable response to it. In addition, because the trial was conducted in an older male population, he questioned whether the results could be generalized to women and younger patients.

The DCP study was funded by the VA Cooperative Studies Program. Dr. Ishani reported no disclosures.

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

There was no difference in major cardiovascular outcomes with the use of two different diuretics – chlorthalidone or hydrochlorothiazide – in the treatment of hypertension in a new large randomized real-world study.

The Diuretic Comparison Project (DCP), which was conducted in more than 13,500 U.S. veterans age 65 years or over, showed almost identical rates of the primary composite endpoint, including myocardial infarction (MI), stroke, noncancer death, hospitalization for acute heart failure, or urgent revascularization, after a median of 2.4 years of follow-up.

There was no difference in any of the individual endpoints or other secondary cardiovascular outcomes.

However, in the subgroup of patients who had a history of MI or stroke (who made up about 10% of the study population), there was a significant reduction in the primary endpoint with chlorthalidone, whereas those without a history of MI or stroke appeared to have an increased risk for primary outcome events while receiving chlorthalidone compared with those receiving hydrochlorothiazide.

The DCP trial was presented at the American Heart Association scientific sessions by Areef Ishani, MD, director of the Minneapolis Primary Care and Specialty Care Integrated Care Community and director of the Veterans Affairs (VA) Midwest Health Care Network.

Asked how to interpret the result for clinical practice, Dr. Ishani said, “I think we can now say that either of these two drugs is appropriate to use for the treatment of hypertension.”

But he added that the decision on what to do with the subgroup of patients with previous MI or stroke was more “challenging.”

“We saw a highly significant benefit in this subgroup, but this was in the context of an overall negative trial,” he noted. “I think this is a discussion with the patients on how they want to hedge their bets. Because these two drugs are so similar, if they wanted to take one or the other because of this subgroup result I think that is a conversation to have, but I think we now need to conduct another trial specifically in this subgroup of patients to see if chlorthalidone really is of benefit in that group.”

Dr. Ishani explained that both chlorthalidone and hydrochlorothiazide have been around for more than 50 years and are considered first-line treatments for hypertension. Early studies suggested better cardiovascular outcomes and 24-hour blood pressure control with chlorthalidone, but recent observational studies have not shown more benefit with chlorthalidone. These studies have suggested that chlorthalidone may be associated with an increase in adverse events, such as hypokalemia, acute kidney injury, and chronic kidney disease.
 

Pragmatic study

The DCP trial was conducted to try to definitively answer this question of whether chlorthalidone is superior to hydrochlorothiazide. The pragmatic study had a “point-of-care” design that allowed participants and health care professionals to know which medication was being prescribed and to administer the medication in a real-world setting.

“Patients can continue with their normal care with their usual care team because we integrated this trial into primary care clinics,” Dr. Ishani said. “We followed participant results using their electronic health record. This study was nonintrusive, cost-effective, and inexpensive. Plus, we were able to recruit a large rural population, which is unusual for large, randomized trials, where we usually rely on big academic medical centers.”

Using VA electronic medical records, the investigators recruited primary care physicians who identified patients older than age 65 years who were receiving hydrochlorothiazide (25 mg or 50 mg) for hypertension. These patients (97% of whom were male) were then randomly assigned to continue receiving hydrochlorothiazide or to switch to an equivalent dose of chlorthalidone. Patients were followed through the electronic medical record as well as Medicare claims and the National Death Index.

Results after a median follow-up of 2.4 years showed no difference in blood pressure control between the two groups.

In terms of clinical events, the primary composite outcome of MI, stroke, noncancer death, hospitalization for acute heart failure, or urgent revascularization occurred in 10.4% of the chlorthalidone group and in 10.0% of the hydrochlorothiazide group (hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.94-1.16; P = .4).

There was no difference in any individual components of the primary endpoint or the secondary outcomes of all-cause mortality, any revascularization, or erectile dysfunction.

In terms of adverse events, chlorthalidone was associated with an increase in hypokalemia (6% vs. 4.4%; HR, 1.38), but there was no difference in hospitalization for acute kidney injury.
 

Benefit in MI, stroke subgroup?

In the subgroup analysis, patients with a history of MI or stroke who were receiving chlorthalidone had a significant 27% reduction in the primary endpoint (HR, 0.73; 95% CI, 0.57-0.94). Conversely, patients without a history of MI or stroke appeared to do worse while taking chlorthalidone (HR, 1.12; 95% CI, 1.00-1.26).

“We were surprised by these results,” Dr. Ishani said. “We expected chlorthalidone to be more effective overall. However, learning about these differences in patients who have a history of cardiovascular disease may affect patient care. It’s best for people to talk with their health care clinicians about which of these medications is better for their individual needs.”

He added: “More research is needed to explore these results further because we don’t know how they may fit into treating the general population.”

Dr. Ishani noted that a limitations of this study was that most patients were receiving the low dose of chlorthalidone, and previous studies that suggested benefits with chlorthalidone used the higher dose.

“But the world has voted – we had 4,000 clinicians involved in this study, and the vast majority are using the low dose of hydrochlorothiazide. And this is a definitively negative study,” he said. “The world has also voted in that 10 times more patients were on hydrochlorothiazide than on chlorthalidone.”

Commenting on the study at an AHA press conference, Biykem Bozkurt, MD, PhD, Baylor College of Medicine, Houston, pointed out that in all of the landmark National Institutes of Health hypertension trials, there was a signal for benefit with chlorthalidone compared with other antihypertensives.

Catherine Hackett/MDedge News

“We’ve always had this concept that chlorthalidone is better,” she said. “But this study shows no difference in major cardiovascular endpoints. There was more hypokalemia with chlorthalidone, but that’s recognizable as chlorthalidone is a more potent diuretic.”

Other limitations of the DCP trial are its open-label design, which could interject some bias; the enduring effects of hydrochlorothiazide – most of these patients were receiving this agent as background therapy; and inability to look at the effectiveness of decongestion of the agents in such a pragmatic study, Dr. Bozkurt noted.

She said she would like to see more analysis in the subgroup of patients with previous MI or stroke. “Does this result mean that chlorthalidone is better for sicker patients or is this result just due to chance?” she asked.

“While this study demonstrates equal effectiveness of these two diuretics in the targeted population, the question of subgroups of patients for which we use a more potent diuretic I think remains unanswered,” she concluded.

Designated discussant of the DCP trial at the late-breaking trial session, Daniel Levy, MD, director of the Framingham Heart Study at the National Heart, Lung, and Blood Institute, reminded attendees that chlorthalidone had shown impressive results in previous important hypertension studies including SHEP and ALLHAT.

He said the current DCP was a pragmatic study addressing a knowledge gap that “would never have been performed by industry.”

Dr. Levy concluded that the results showing no difference in outcomes between the two diuretics were “compelling,” although a few questions remain.

These include a possible bias toward hydrochlorothiazide – patients were selected who were already taking that drug and so would have already had a favorable response to it. In addition, because the trial was conducted in an older male population, he questioned whether the results could be generalized to women and younger patients.

The DCP study was funded by the VA Cooperative Studies Program. Dr. Ishani reported no disclosures.

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

CHICAGO – Despite a 25% reduction in triglycerides (TGs) along with similar reductions in very-low-density lipoprotein (VLDL), and remnant cholesterol, a novel agent failed to provide any protection in a multinational trial against a composite endpoint of major adverse cardiovascular events (MACE) in patients with type 2 diabetes.

“Our data further highlight the complexity of lipid mediators of residual risk among patients with insulin resistance who are receiving statin therapy,” reported Aruna Das Pradhan, MD, of Harvard Medical School, Boston, and Queen Mary University, London.

Ted Bosworth/MDedge News

No benefit from fibrates seen in statin era

“We have not seen a significant cardiovascular event reduction with a fibrate in the statin era,” according to Karol Watson, MD, PhD, director of the UCLA Women’s Cardiovascular Health Center, Los Angeles.

Ted Bosworth/MDedge News

Lipid profile improved as predicted

Yet, in regard to an improvement in the lipid profile, pemafibrate performed as predicted. When compared to placebo 4 months into the trial, pemafibrate was associated with median reductions of 26.2% in TGs, 25.8% in VLDL, and 25.6% in remnant cholesterol, which is cholesterol transported in TG-rich lipoproteins after lipolysis and lipoprotein remodeling.

Furthermore, pemafibrate was associated with a median 27.6% reduction relative to placebo in apolipoprotein C-III and a median 4.8% reduction in apolipoprotein E, all of which would be expected to reduce CV risk.

The findings of PROMINENT were published online in the New England Journal of Medicine immediately after their presentation.

The findings of this study do not eliminate any hope for lowering residual CV risk with TG reductions, but they do suggest the relationship with other lipid subfractions is complex, according to Salim S. Virani, MD, PhD, a professor of cardiology at Baylor College of Medicine, Houston.

“I think that the lack of efficacy despite TG lowering may be largely due to a lack of an overall decrease in the apolipoprotein B level,” speculated Dr. Virani, who wrote an editorial that accompanied publication of the PROMINENT results.

He noted that pemafibrate is implicated in converting remnant cholesterol to LDL cholesterol, which might be one reason for a counterproductive effect on CV risk.

“In order for therapies that lower TG levels to be effective, they probably have to have mechanisms to increase clearance of TG-rich remnant lipoprotein cholesterol particles rather than just converting remnant lipoproteins to LDL,” Dr. Virani explained in an attempt to unravel the interplay of these variables.

Although this study enrolled patients “who would be predicted to have the most benefit from a TG-lowering strategy,” Dr. Watson agreed that these results do not necessarily extend to other means of lowering TG. However, it might draw into question the value of pemafibrate and perhaps other drugs in this class for treatment of hypertriglyceridemia. In addition to a lack of CV benefit, treatment was not without risks, including a higher rate of thromboembolism and adverse renal events.

Dr. Das Pradhan reported financial relationships with Denka, Medtelligence, Optum, Novo Nordisk, and Kowa, which provided funding for this trial. Dr. Watson reported financial relationships with Amarin, Amgen, Boehringer-Ingelheim, and Esperion.

CHICAGO – Despite a 25% reduction in triglycerides (TGs) along with similar reductions in very-low-density lipoprotein (VLDL), and remnant cholesterol, a novel agent failed to provide any protection in a multinational trial against a composite endpoint of major adverse cardiovascular events (MACE) in patients with type 2 diabetes.

“Our data further highlight the complexity of lipid mediators of residual risk among patients with insulin resistance who are receiving statin therapy,” reported Aruna Das Pradhan, MD, of Harvard Medical School, Boston, and Queen Mary University, London.

Ted Bosworth/MDedge News

No benefit from fibrates seen in statin era

“We have not seen a significant cardiovascular event reduction with a fibrate in the statin era,” according to Karol Watson, MD, PhD, director of the UCLA Women’s Cardiovascular Health Center, Los Angeles.

Ted Bosworth/MDedge News

Lipid profile improved as predicted

Yet, in regard to an improvement in the lipid profile, pemafibrate performed as predicted. When compared to placebo 4 months into the trial, pemafibrate was associated with median reductions of 26.2% in TGs, 25.8% in VLDL, and 25.6% in remnant cholesterol, which is cholesterol transported in TG-rich lipoproteins after lipolysis and lipoprotein remodeling.

Furthermore, pemafibrate was associated with a median 27.6% reduction relative to placebo in apolipoprotein C-III and a median 4.8% reduction in apolipoprotein E, all of which would be expected to reduce CV risk.

The findings of PROMINENT were published online in the New England Journal of Medicine immediately after their presentation.

The findings of this study do not eliminate any hope for lowering residual CV risk with TG reductions, but they do suggest the relationship with other lipid subfractions is complex, according to Salim S. Virani, MD, PhD, a professor of cardiology at Baylor College of Medicine, Houston.

“I think that the lack of efficacy despite TG lowering may be largely due to a lack of an overall decrease in the apolipoprotein B level,” speculated Dr. Virani, who wrote an editorial that accompanied publication of the PROMINENT results.

He noted that pemafibrate is implicated in converting remnant cholesterol to LDL cholesterol, which might be one reason for a counterproductive effect on CV risk.

“In order for therapies that lower TG levels to be effective, they probably have to have mechanisms to increase clearance of TG-rich remnant lipoprotein cholesterol particles rather than just converting remnant lipoproteins to LDL,” Dr. Virani explained in an attempt to unravel the interplay of these variables.

Although this study enrolled patients “who would be predicted to have the most benefit from a TG-lowering strategy,” Dr. Watson agreed that these results do not necessarily extend to other means of lowering TG. However, it might draw into question the value of pemafibrate and perhaps other drugs in this class for treatment of hypertriglyceridemia. In addition to a lack of CV benefit, treatment was not without risks, including a higher rate of thromboembolism and adverse renal events.

Dr. Das Pradhan reported financial relationships with Denka, Medtelligence, Optum, Novo Nordisk, and Kowa, which provided funding for this trial. Dr. Watson reported financial relationships with Amarin, Amgen, Boehringer-Ingelheim, and Esperion.

CHICAGO – Despite a 25% reduction in triglycerides (TGs) along with similar reductions in very-low-density lipoprotein (VLDL), and remnant cholesterol, a novel agent failed to provide any protection in a multinational trial against a composite endpoint of major adverse cardiovascular events (MACE) in patients with type 2 diabetes.

“Our data further highlight the complexity of lipid mediators of residual risk among patients with insulin resistance who are receiving statin therapy,” reported Aruna Das Pradhan, MD, of Harvard Medical School, Boston, and Queen Mary University, London.

Ted Bosworth/MDedge News

No benefit from fibrates seen in statin era

“We have not seen a significant cardiovascular event reduction with a fibrate in the statin era,” according to Karol Watson, MD, PhD, director of the UCLA Women’s Cardiovascular Health Center, Los Angeles.

Ted Bosworth/MDedge News

Lipid profile improved as predicted

Yet, in regard to an improvement in the lipid profile, pemafibrate performed as predicted. When compared to placebo 4 months into the trial, pemafibrate was associated with median reductions of 26.2% in TGs, 25.8% in VLDL, and 25.6% in remnant cholesterol, which is cholesterol transported in TG-rich lipoproteins after lipolysis and lipoprotein remodeling.

Furthermore, pemafibrate was associated with a median 27.6% reduction relative to placebo in apolipoprotein C-III and a median 4.8% reduction in apolipoprotein E, all of which would be expected to reduce CV risk.

The findings of PROMINENT were published online in the New England Journal of Medicine immediately after their presentation.

The findings of this study do not eliminate any hope for lowering residual CV risk with TG reductions, but they do suggest the relationship with other lipid subfractions is complex, according to Salim S. Virani, MD, PhD, a professor of cardiology at Baylor College of Medicine, Houston.

“I think that the lack of efficacy despite TG lowering may be largely due to a lack of an overall decrease in the apolipoprotein B level,” speculated Dr. Virani, who wrote an editorial that accompanied publication of the PROMINENT results.

He noted that pemafibrate is implicated in converting remnant cholesterol to LDL cholesterol, which might be one reason for a counterproductive effect on CV risk.

“In order for therapies that lower TG levels to be effective, they probably have to have mechanisms to increase clearance of TG-rich remnant lipoprotein cholesterol particles rather than just converting remnant lipoproteins to LDL,” Dr. Virani explained in an attempt to unravel the interplay of these variables.

Although this study enrolled patients “who would be predicted to have the most benefit from a TG-lowering strategy,” Dr. Watson agreed that these results do not necessarily extend to other means of lowering TG. However, it might draw into question the value of pemafibrate and perhaps other drugs in this class for treatment of hypertriglyceridemia. In addition to a lack of CV benefit, treatment was not without risks, including a higher rate of thromboembolism and adverse renal events.

Dr. Das Pradhan reported financial relationships with Denka, Medtelligence, Optum, Novo Nordisk, and Kowa, which provided funding for this trial. Dr. Watson reported financial relationships with Amarin, Amgen, Boehringer-Ingelheim, and Esperion.