User login
ISCHEMIA-EXTEND: Conservative stable CAD management holds up
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.
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.
“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.
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.
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.
“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.
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.
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.
“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.
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.
AT AHA 2022
Study sheds new light on RAS inhibitors’ role for advanced CKD
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, , 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, , 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, , 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.
AT KIDNEY WEEK 2022
Moving the needle: SGLT2 inhibitor role for isolated kidney disease
ORLANDO – in a pivotal trial with more than 6,600 patients.
This confirms the efficacy for this population that was previously seen with dapagliflozin, another agent from the same class, in the DAPA-CKD trial.
In the new trial, EMPA-Kidney, treatment with empagliflozin 10 mg daily for a median of 2.0 years led to a significant 28% relative risk reduction in the primary combined endpoint in comparison with placebo, William G. Herrington, MD, reported at the annual meeting of the American Society of Nephrology.
The results were simultaneously published in the New England Journal of Medicine.
In 2020, a different team of researchers running DAPA-CKD reported that during a median of 2.4 years, treatment of 4,304 patients with dapagliflozin 10 mg daily resulted in a significant 39% relative risk reduction, compared with placebo for an identical combined primary endpoint. Enrollment criteria for the DAPA-CKD trial were mostly similar to that of the current trial.
‘Remarkably similar’ findings
Results from EMPA-Kidney and DAPA-CKD are “remarkably similar,” said Dr. Herrington during a press briefing at the meeting.
He also noted that when the EMPA-Kidney study began – before results from DAPA-CKD were known – “we never imagined such a large effect” on important endpoints in people with CKD.
In addition to cardiovascular death, the combined primary endpoint included the incidence of renal death, incident end-stage kidney disease, a sustained decrease in estimated glomerular filtration rate to less than 10 mL/min per 1.73m2, or a sustained decrease in eGFR of at least 40% from baseline.
Having similar evidence from both trials “will hopefully provide people with the confidence to start to use SGLT2 inhibitors as standard care in people with CKD” who match enrollment criteria of the two trials, added Dr. Herrington, a nephrologist at the University of Oxford (England).
The analyses he reported also showed that empagliflozin had similar efficacy for the primary endpoint regardless of whether patients had type 2 diabetes at the time of enrollment and regardless of their eGFR at entry.
To enter EMPA-Kidney, people needed to have either an eGFR of 20-44 mL/min per 1.73m2 with no minimum level of albuminuria or an eGFR of 45-89 mL/min per 1.73m2 with a urine albumin-to-creatinine ratio (UACR) of at least 200 mg/g.
In contrast, to enroll in DAPA-CKD, patients had to have a UACR of at least 200 mg/g. This means that for the first time, EMPA-Kidney produced data on the relationship between albuminuria severity and the impact of treatment with an SGLT2 inhibitor in the enrolled population.
A signal of greater efficacy with higher UACR
A total of 6,609 patients underwent randomization in EMPA-Kidney. During a median of 2.0 years of follow-up, the primary endpoint – progression of kidney disease or death from cardiovascular causes – occurred in 432 of 3,304 patients (13.1%) in the empagliflozin group and in 558 of 3,305 patients (16.9%) in the placebo group (hazard ratio, 0.72; P < .001).
The results “suggested that the effects [of empagliflozin] are greater in patients with higher levels of albuminuria, with statistically significant heterogeneity between this subgroup and those with a UACR of less than 200 mg/g (P = .02),” Dr. Herrington said.
Of the study population, 54% had no evidence of diabetes at enrollment.
Having data from a second large trial of an SGLT2 inhibitor that included people with isolated CKD who did not have diabetes or heart failure “will start to move the needle” on using this class of drugs in these types of patients, commented F. Perry Wilson, MD, a nephrologist at Yale University, New Haven, Conn.
On the basis of the DAPA-CKD results, in April 2021 the Food and Drug Administration expanded dapagliflozin’s indications to include CKD, yet, “a lot of nephrologists consider SGLT2 inhibitors to be agents for people with diabetes or heart failure, and they defer prescribing them to endocrinologists and cardiologists,” Dr. Wilson said in an interview.
‘Flozinators’ rising
But Pascale H. Lane, MD, a pediatric nephrologist at the University of Oklahoma Health Sciences Center, Oklahoma City, commented that many nephrologists she knows have been prescribing dapagliflozin “widely” to their patients with CKD.
“I know many adult nephrologists who use it almost universally now,” Dr. Lane said. “They call themselves ‘flozinators.’ ”
EMPA-Kidney was sponsored by Boehringer Ingelheim, the company that along with Lilly markets empagliflozin (Jardiance). Dr. Herrington, Dr. Wilson, and Dr. Lane disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
ORLANDO – in a pivotal trial with more than 6,600 patients.
This confirms the efficacy for this population that was previously seen with dapagliflozin, another agent from the same class, in the DAPA-CKD trial.
In the new trial, EMPA-Kidney, treatment with empagliflozin 10 mg daily for a median of 2.0 years led to a significant 28% relative risk reduction in the primary combined endpoint in comparison with placebo, William G. Herrington, MD, reported at the annual meeting of the American Society of Nephrology.
The results were simultaneously published in the New England Journal of Medicine.
In 2020, a different team of researchers running DAPA-CKD reported that during a median of 2.4 years, treatment of 4,304 patients with dapagliflozin 10 mg daily resulted in a significant 39% relative risk reduction, compared with placebo for an identical combined primary endpoint. Enrollment criteria for the DAPA-CKD trial were mostly similar to that of the current trial.
‘Remarkably similar’ findings
Results from EMPA-Kidney and DAPA-CKD are “remarkably similar,” said Dr. Herrington during a press briefing at the meeting.
He also noted that when the EMPA-Kidney study began – before results from DAPA-CKD were known – “we never imagined such a large effect” on important endpoints in people with CKD.
In addition to cardiovascular death, the combined primary endpoint included the incidence of renal death, incident end-stage kidney disease, a sustained decrease in estimated glomerular filtration rate to less than 10 mL/min per 1.73m2, or a sustained decrease in eGFR of at least 40% from baseline.
Having similar evidence from both trials “will hopefully provide people with the confidence to start to use SGLT2 inhibitors as standard care in people with CKD” who match enrollment criteria of the two trials, added Dr. Herrington, a nephrologist at the University of Oxford (England).
The analyses he reported also showed that empagliflozin had similar efficacy for the primary endpoint regardless of whether patients had type 2 diabetes at the time of enrollment and regardless of their eGFR at entry.
To enter EMPA-Kidney, people needed to have either an eGFR of 20-44 mL/min per 1.73m2 with no minimum level of albuminuria or an eGFR of 45-89 mL/min per 1.73m2 with a urine albumin-to-creatinine ratio (UACR) of at least 200 mg/g.
In contrast, to enroll in DAPA-CKD, patients had to have a UACR of at least 200 mg/g. This means that for the first time, EMPA-Kidney produced data on the relationship between albuminuria severity and the impact of treatment with an SGLT2 inhibitor in the enrolled population.
A signal of greater efficacy with higher UACR
A total of 6,609 patients underwent randomization in EMPA-Kidney. During a median of 2.0 years of follow-up, the primary endpoint – progression of kidney disease or death from cardiovascular causes – occurred in 432 of 3,304 patients (13.1%) in the empagliflozin group and in 558 of 3,305 patients (16.9%) in the placebo group (hazard ratio, 0.72; P < .001).
The results “suggested that the effects [of empagliflozin] are greater in patients with higher levels of albuminuria, with statistically significant heterogeneity between this subgroup and those with a UACR of less than 200 mg/g (P = .02),” Dr. Herrington said.
Of the study population, 54% had no evidence of diabetes at enrollment.
Having data from a second large trial of an SGLT2 inhibitor that included people with isolated CKD who did not have diabetes or heart failure “will start to move the needle” on using this class of drugs in these types of patients, commented F. Perry Wilson, MD, a nephrologist at Yale University, New Haven, Conn.
On the basis of the DAPA-CKD results, in April 2021 the Food and Drug Administration expanded dapagliflozin’s indications to include CKD, yet, “a lot of nephrologists consider SGLT2 inhibitors to be agents for people with diabetes or heart failure, and they defer prescribing them to endocrinologists and cardiologists,” Dr. Wilson said in an interview.
‘Flozinators’ rising
But Pascale H. Lane, MD, a pediatric nephrologist at the University of Oklahoma Health Sciences Center, Oklahoma City, commented that many nephrologists she knows have been prescribing dapagliflozin “widely” to their patients with CKD.
“I know many adult nephrologists who use it almost universally now,” Dr. Lane said. “They call themselves ‘flozinators.’ ”
EMPA-Kidney was sponsored by Boehringer Ingelheim, the company that along with Lilly markets empagliflozin (Jardiance). Dr. Herrington, Dr. Wilson, and Dr. Lane disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
ORLANDO – in a pivotal trial with more than 6,600 patients.
This confirms the efficacy for this population that was previously seen with dapagliflozin, another agent from the same class, in the DAPA-CKD trial.
In the new trial, EMPA-Kidney, treatment with empagliflozin 10 mg daily for a median of 2.0 years led to a significant 28% relative risk reduction in the primary combined endpoint in comparison with placebo, William G. Herrington, MD, reported at the annual meeting of the American Society of Nephrology.
The results were simultaneously published in the New England Journal of Medicine.
In 2020, a different team of researchers running DAPA-CKD reported that during a median of 2.4 years, treatment of 4,304 patients with dapagliflozin 10 mg daily resulted in a significant 39% relative risk reduction, compared with placebo for an identical combined primary endpoint. Enrollment criteria for the DAPA-CKD trial were mostly similar to that of the current trial.
‘Remarkably similar’ findings
Results from EMPA-Kidney and DAPA-CKD are “remarkably similar,” said Dr. Herrington during a press briefing at the meeting.
He also noted that when the EMPA-Kidney study began – before results from DAPA-CKD were known – “we never imagined such a large effect” on important endpoints in people with CKD.
In addition to cardiovascular death, the combined primary endpoint included the incidence of renal death, incident end-stage kidney disease, a sustained decrease in estimated glomerular filtration rate to less than 10 mL/min per 1.73m2, or a sustained decrease in eGFR of at least 40% from baseline.
Having similar evidence from both trials “will hopefully provide people with the confidence to start to use SGLT2 inhibitors as standard care in people with CKD” who match enrollment criteria of the two trials, added Dr. Herrington, a nephrologist at the University of Oxford (England).
The analyses he reported also showed that empagliflozin had similar efficacy for the primary endpoint regardless of whether patients had type 2 diabetes at the time of enrollment and regardless of their eGFR at entry.
To enter EMPA-Kidney, people needed to have either an eGFR of 20-44 mL/min per 1.73m2 with no minimum level of albuminuria or an eGFR of 45-89 mL/min per 1.73m2 with a urine albumin-to-creatinine ratio (UACR) of at least 200 mg/g.
In contrast, to enroll in DAPA-CKD, patients had to have a UACR of at least 200 mg/g. This means that for the first time, EMPA-Kidney produced data on the relationship between albuminuria severity and the impact of treatment with an SGLT2 inhibitor in the enrolled population.
A signal of greater efficacy with higher UACR
A total of 6,609 patients underwent randomization in EMPA-Kidney. During a median of 2.0 years of follow-up, the primary endpoint – progression of kidney disease or death from cardiovascular causes – occurred in 432 of 3,304 patients (13.1%) in the empagliflozin group and in 558 of 3,305 patients (16.9%) in the placebo group (hazard ratio, 0.72; P < .001).
The results “suggested that the effects [of empagliflozin] are greater in patients with higher levels of albuminuria, with statistically significant heterogeneity between this subgroup and those with a UACR of less than 200 mg/g (P = .02),” Dr. Herrington said.
Of the study population, 54% had no evidence of diabetes at enrollment.
Having data from a second large trial of an SGLT2 inhibitor that included people with isolated CKD who did not have diabetes or heart failure “will start to move the needle” on using this class of drugs in these types of patients, commented F. Perry Wilson, MD, a nephrologist at Yale University, New Haven, Conn.
On the basis of the DAPA-CKD results, in April 2021 the Food and Drug Administration expanded dapagliflozin’s indications to include CKD, yet, “a lot of nephrologists consider SGLT2 inhibitors to be agents for people with diabetes or heart failure, and they defer prescribing them to endocrinologists and cardiologists,” Dr. Wilson said in an interview.
‘Flozinators’ rising
But Pascale H. Lane, MD, a pediatric nephrologist at the University of Oklahoma Health Sciences Center, Oklahoma City, commented that many nephrologists she knows have been prescribing dapagliflozin “widely” to their patients with CKD.
“I know many adult nephrologists who use it almost universally now,” Dr. Lane said. “They call themselves ‘flozinators.’ ”
EMPA-Kidney was sponsored by Boehringer Ingelheim, the company that along with Lilly markets empagliflozin (Jardiance). Dr. Herrington, Dr. Wilson, and Dr. Lane disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AT KIDNEY WEEK 2022
Acute heart failure risk assessment in ED improves outcomes: COACH
CHICAGO – Systematic mortality-risk assessment of patients who presented to hospital emergency departments for acute heart failure led to better patient outcomes in a controlled Canadian trial with more than 5,000 patients.
Thirty days after patients presented, the incidence of death from any cause or hospitalization for cardiovascular causes – one of two primary endpoints in the COACH study – was 12.1% among patients who underwent acute risk assessment and 14.5% in control patients who did not undergo this assessment, which translated into an adjusted, significant 12% relative risk reduction for the patients who underwent systematic assessment, Douglas S. Lee, MD, PhD, said at the American Heart Association scientific sessions.
The study’s second primary endpoint, the incidence of the same combined outcome 20 months after initial presentation, was 54.4% among the 2,480 patients assessed with the risk-assessment tool and 56.2% in the 2,972 controls, a significant, adjusted relative risk reduction of 5%.
This benefit was primarily driven by reductions in cardiovascular hospitalizations, which fell by an adjusted 16% in the intervention group compared with controls, and more specifically by hospitalizations for heart failure, which tallied a relative 20% less with the intervention. Both were significant between-group differences.
The other portion of the combined endpoint, all-cause mortality, was not significantly different between the patients who underwent the systematic emergency department assessment and the controls who were managed using usual emergency-department protocols.
Simultaneous with the report, the results also appeared online in the New England Journal of Medicine.
A pathway for early discharge and improved outcomes
“Implementation of this approach may lead to a pathway for early discharge from the hospital or emergency department, and improved patient outcomes,” said Dr. Lee, a professor at the University of Toronto, and a senior core scientist at the ICES Cardiovascular Research Program in Toronto.
“The treatment effect on the primary process outcome – patients admitted or discharged – will add useful insights into how intervention may improve,” commented Harriette Van Spall, MD, who was designated discussant for the report. The findings “fill an important knowledge gap,” added Dr. Van Spall, a cardiologist at McMaster University in Hamilton, Ont. The results “have important implications for health resource utilization,” she said.
The risk assessment tool used in the study is called the Emergency Heart failure Mortality Risk Grade for 30-day mortality (EHMRG30-ST), which was devised and validated by Dr. Lee and his associates. The assessment tool uses 11 clinical variables that include age, systolic blood pressure, heart rate, oxygen saturation, potassium and creatinine levels, and presence of ST depression on a 12-lead ECG.
The study design recommended that patients be discharged early and receive standardized transitional care as outpatients if they had a low risk of death within 7 days and within 30 days as estimated by the EHMRG30-ST. The protocol recommended that patients scored as high risk should be admitted to the hospital, and that clinicians use their clinical judgment for intermediate-risk patients but favor admission for intermediate to high risk and discharge for low to intermediate risk. The study ran at 10 hospitals in Ontario. Initially, all 10 hospitals assessed patients by usual care, and then, over time, each hospital began using the tool so that by the end of the study all 10 hospitals employed it. Among the 2,480 patients seen during the active phase, 2,442 actually underwent assessment, with 24% rated as low risk, 32% rated as intermediate risk, and 44% judged to have high risk.
The researchers also ran risk assessments retrospectively on the controls, who showed a roughly similar risk distribution, with 18% low risk, 28% intermediate risk, and 54% high risk.
The patients averaged 78 years of age, 55% were men, about 40% had diabetes, and about 64% had a prior heart failure diagnosis.
Heart failure admissions have become ‘a big deal’
Emergency department clinicians and heart failure cardiologists “have worked together for a long time” when making decisions about which patients with acute heart failure need hospital admission, commented Mary N. Walsh, MD, medical director of the heart failure and cardiac transplantation programs at Ascension St. Vincent Heart Center in Indianapolis. These decisions “became a big deal” a decade ago when the U.S. Centers for Medicare & Medicaid Services launched the Hospital Readmissions Reduction Program that began to penalize hospitals for high rates of hospital readmissions for several conditions including heart failure, she said in an interview.
“If a heart failure patient is not admitted, they can’t be readmitted,” Dr. Walsh noted.
“Many risk-assessment tools exist for patients once they are hospitalized, but these tools have not been used in emergency departments. The take-home message is that we need to start risk assessment sooner, in the emergency department,” she said.
But the specific approach tested in the COACH trial needs more study and may need further tweaking to work in the United States, where it is not clear who would pay for a program like the one tested in the trial. Canada’s unified health care payment system makes the COACH approach more financially feasible, Dr. Walsh commented.
COACH received no commercial funding. Dr. Lee, Dr. Van Spall, and Dr. Walsh had no disclosures.
CHICAGO – Systematic mortality-risk assessment of patients who presented to hospital emergency departments for acute heart failure led to better patient outcomes in a controlled Canadian trial with more than 5,000 patients.
Thirty days after patients presented, the incidence of death from any cause or hospitalization for cardiovascular causes – one of two primary endpoints in the COACH study – was 12.1% among patients who underwent acute risk assessment and 14.5% in control patients who did not undergo this assessment, which translated into an adjusted, significant 12% relative risk reduction for the patients who underwent systematic assessment, Douglas S. Lee, MD, PhD, said at the American Heart Association scientific sessions.
The study’s second primary endpoint, the incidence of the same combined outcome 20 months after initial presentation, was 54.4% among the 2,480 patients assessed with the risk-assessment tool and 56.2% in the 2,972 controls, a significant, adjusted relative risk reduction of 5%.
This benefit was primarily driven by reductions in cardiovascular hospitalizations, which fell by an adjusted 16% in the intervention group compared with controls, and more specifically by hospitalizations for heart failure, which tallied a relative 20% less with the intervention. Both were significant between-group differences.
The other portion of the combined endpoint, all-cause mortality, was not significantly different between the patients who underwent the systematic emergency department assessment and the controls who were managed using usual emergency-department protocols.
Simultaneous with the report, the results also appeared online in the New England Journal of Medicine.
A pathway for early discharge and improved outcomes
“Implementation of this approach may lead to a pathway for early discharge from the hospital or emergency department, and improved patient outcomes,” said Dr. Lee, a professor at the University of Toronto, and a senior core scientist at the ICES Cardiovascular Research Program in Toronto.
“The treatment effect on the primary process outcome – patients admitted or discharged – will add useful insights into how intervention may improve,” commented Harriette Van Spall, MD, who was designated discussant for the report. The findings “fill an important knowledge gap,” added Dr. Van Spall, a cardiologist at McMaster University in Hamilton, Ont. The results “have important implications for health resource utilization,” she said.
The risk assessment tool used in the study is called the Emergency Heart failure Mortality Risk Grade for 30-day mortality (EHMRG30-ST), which was devised and validated by Dr. Lee and his associates. The assessment tool uses 11 clinical variables that include age, systolic blood pressure, heart rate, oxygen saturation, potassium and creatinine levels, and presence of ST depression on a 12-lead ECG.
The study design recommended that patients be discharged early and receive standardized transitional care as outpatients if they had a low risk of death within 7 days and within 30 days as estimated by the EHMRG30-ST. The protocol recommended that patients scored as high risk should be admitted to the hospital, and that clinicians use their clinical judgment for intermediate-risk patients but favor admission for intermediate to high risk and discharge for low to intermediate risk. The study ran at 10 hospitals in Ontario. Initially, all 10 hospitals assessed patients by usual care, and then, over time, each hospital began using the tool so that by the end of the study all 10 hospitals employed it. Among the 2,480 patients seen during the active phase, 2,442 actually underwent assessment, with 24% rated as low risk, 32% rated as intermediate risk, and 44% judged to have high risk.
The researchers also ran risk assessments retrospectively on the controls, who showed a roughly similar risk distribution, with 18% low risk, 28% intermediate risk, and 54% high risk.
The patients averaged 78 years of age, 55% were men, about 40% had diabetes, and about 64% had a prior heart failure diagnosis.
Heart failure admissions have become ‘a big deal’
Emergency department clinicians and heart failure cardiologists “have worked together for a long time” when making decisions about which patients with acute heart failure need hospital admission, commented Mary N. Walsh, MD, medical director of the heart failure and cardiac transplantation programs at Ascension St. Vincent Heart Center in Indianapolis. These decisions “became a big deal” a decade ago when the U.S. Centers for Medicare & Medicaid Services launched the Hospital Readmissions Reduction Program that began to penalize hospitals for high rates of hospital readmissions for several conditions including heart failure, she said in an interview.
“If a heart failure patient is not admitted, they can’t be readmitted,” Dr. Walsh noted.
“Many risk-assessment tools exist for patients once they are hospitalized, but these tools have not been used in emergency departments. The take-home message is that we need to start risk assessment sooner, in the emergency department,” she said.
But the specific approach tested in the COACH trial needs more study and may need further tweaking to work in the United States, where it is not clear who would pay for a program like the one tested in the trial. Canada’s unified health care payment system makes the COACH approach more financially feasible, Dr. Walsh commented.
COACH received no commercial funding. Dr. Lee, Dr. Van Spall, and Dr. Walsh had no disclosures.
CHICAGO – Systematic mortality-risk assessment of patients who presented to hospital emergency departments for acute heart failure led to better patient outcomes in a controlled Canadian trial with more than 5,000 patients.
Thirty days after patients presented, the incidence of death from any cause or hospitalization for cardiovascular causes – one of two primary endpoints in the COACH study – was 12.1% among patients who underwent acute risk assessment and 14.5% in control patients who did not undergo this assessment, which translated into an adjusted, significant 12% relative risk reduction for the patients who underwent systematic assessment, Douglas S. Lee, MD, PhD, said at the American Heart Association scientific sessions.
The study’s second primary endpoint, the incidence of the same combined outcome 20 months after initial presentation, was 54.4% among the 2,480 patients assessed with the risk-assessment tool and 56.2% in the 2,972 controls, a significant, adjusted relative risk reduction of 5%.
This benefit was primarily driven by reductions in cardiovascular hospitalizations, which fell by an adjusted 16% in the intervention group compared with controls, and more specifically by hospitalizations for heart failure, which tallied a relative 20% less with the intervention. Both were significant between-group differences.
The other portion of the combined endpoint, all-cause mortality, was not significantly different between the patients who underwent the systematic emergency department assessment and the controls who were managed using usual emergency-department protocols.
Simultaneous with the report, the results also appeared online in the New England Journal of Medicine.
A pathway for early discharge and improved outcomes
“Implementation of this approach may lead to a pathway for early discharge from the hospital or emergency department, and improved patient outcomes,” said Dr. Lee, a professor at the University of Toronto, and a senior core scientist at the ICES Cardiovascular Research Program in Toronto.
“The treatment effect on the primary process outcome – patients admitted or discharged – will add useful insights into how intervention may improve,” commented Harriette Van Spall, MD, who was designated discussant for the report. The findings “fill an important knowledge gap,” added Dr. Van Spall, a cardiologist at McMaster University in Hamilton, Ont. The results “have important implications for health resource utilization,” she said.
The risk assessment tool used in the study is called the Emergency Heart failure Mortality Risk Grade for 30-day mortality (EHMRG30-ST), which was devised and validated by Dr. Lee and his associates. The assessment tool uses 11 clinical variables that include age, systolic blood pressure, heart rate, oxygen saturation, potassium and creatinine levels, and presence of ST depression on a 12-lead ECG.
The study design recommended that patients be discharged early and receive standardized transitional care as outpatients if they had a low risk of death within 7 days and within 30 days as estimated by the EHMRG30-ST. The protocol recommended that patients scored as high risk should be admitted to the hospital, and that clinicians use their clinical judgment for intermediate-risk patients but favor admission for intermediate to high risk and discharge for low to intermediate risk. The study ran at 10 hospitals in Ontario. Initially, all 10 hospitals assessed patients by usual care, and then, over time, each hospital began using the tool so that by the end of the study all 10 hospitals employed it. Among the 2,480 patients seen during the active phase, 2,442 actually underwent assessment, with 24% rated as low risk, 32% rated as intermediate risk, and 44% judged to have high risk.
The researchers also ran risk assessments retrospectively on the controls, who showed a roughly similar risk distribution, with 18% low risk, 28% intermediate risk, and 54% high risk.
The patients averaged 78 years of age, 55% were men, about 40% had diabetes, and about 64% had a prior heart failure diagnosis.
Heart failure admissions have become ‘a big deal’
Emergency department clinicians and heart failure cardiologists “have worked together for a long time” when making decisions about which patients with acute heart failure need hospital admission, commented Mary N. Walsh, MD, medical director of the heart failure and cardiac transplantation programs at Ascension St. Vincent Heart Center in Indianapolis. These decisions “became a big deal” a decade ago when the U.S. Centers for Medicare & Medicaid Services launched the Hospital Readmissions Reduction Program that began to penalize hospitals for high rates of hospital readmissions for several conditions including heart failure, she said in an interview.
“If a heart failure patient is not admitted, they can’t be readmitted,” Dr. Walsh noted.
“Many risk-assessment tools exist for patients once they are hospitalized, but these tools have not been used in emergency departments. The take-home message is that we need to start risk assessment sooner, in the emergency department,” she said.
But the specific approach tested in the COACH trial needs more study and may need further tweaking to work in the United States, where it is not clear who would pay for a program like the one tested in the trial. Canada’s unified health care payment system makes the COACH approach more financially feasible, Dr. Walsh commented.
COACH received no commercial funding. Dr. Lee, Dr. Van Spall, and Dr. Walsh had no disclosures.
AT AHA 2022
USPSTF holds firm on postmenopausal hormone recommendations
The U.S. Preventive Services Task Force moved forward their recommendations for using hormone therapy to prevent chronic conditions in postmenopausal women by keeping them the same.
The central message of the new recommendations, released on Nov. 1 as a statement published in JAMA, remains unchanged from the last update in 2017.
The message also remains simple: Don’t use hormone therapy for preventing chronic conditions, such as cardiovascular disease, cancer, and osteoporosis, or bone fracture.
The USPSTF summarized its recommendations in two brief statements: the group “recommends against the use of combined estrogen and progestin for the primary prevention of chronic conditions in postmenopausal persons” and “recommends against the use of estrogen alone for the primary prevention of chronic conditions in postmenopausal persons who have had a hysterectomy.”
This wording is identical to that used in the 2017 guidance (except it now refers to postmenopausal persons instead of specifically women). The recommendation against use of estrogen and progestin for prevention of chronic conditions in postmenopausal women was first made by the USPSTF in 2002.
An editorial accompanying the 2022 revision notes that the evidence cited by the USPSTF includes “only two additional, modest-sized trials” (that focused on the effects of hormone therapy on cognition and brain structure) compared with 2017, “as well as ancillary analyses of previous trials.”
A standard 5-year update
The 2022 revision and revisiting of the evidence base by the Task Force regarding the benefits and risks of postmenopausal hormone therapy occurred “as part of the Task Force’s standard approach, which includes updating each recommendation approximately every 5 years,” explained Carol M. Mangione, MD, who is USPSTF chair and chief of the division of general internal medicine and health services research at the University of California, Los Angeles.
“In our review we again found that while hormone therapy may reduce the risk of some conditions, it can also lead to serious harms such as an increase in the risk of blood clots and stroke,” Dr. Mangione said in an interview. “The harms cancel out any potential benefits overall.”
This new statement only applies to using menopausal hormone treatment for preventing chronic conditions in asymptomatic people but does not speak to using this treatment in managing people with perimenopausal symptoms such as hot flashes or vaginal dryness or treating people with premature or surgical menopause, Dr. Mangione highlighted.
No review for treating menopausal symptoms
“The Task Force encourages people who are experiencing symptoms of menopause to talk with their health care professional about the best treatment for them,” explained Dr. Mangione. “The Task Force did not review the evidence on the use of hormone therapy to treat symptoms of menopause.”
Osteoporosis and increased risk for bone fracture were among the conditions that accompany menopause reviewed by the USPSTF. The Task Force concluded that while “hormone therapy was associated with decreased risk of fractures,” after weighing the benefits and harms for preventing this condition, “there is no net benefit at the population level.”
This conclusion seems to contrast with the 2022 hormone therapy position statement of the North American Menopause Society (NAMS), released in July, which states: “For women aged younger than 60 years or who are within 10 years of menopause onset and have no contraindications, the benefit-risk ratio is favorable for treatment of bothersome vasomotor symptoms and prevention of bone loss.”
USPSTF, NAMS are ‘completely consistent’
However, Stephanie S. Faubion, MD, medical director of NAMS and director of the women’s health clinic at Mayo Clinic, Rochester, Minn., said the new USPSTF recommendations “are completely consistent” with the recent NAMS statement.
“We are entirely aligned with the recommendation to use hormone therapy for management of menopausal symptoms and not for chronic disease prevention or as an anti-aging strategy,” Dr. Faubion commented in an interview.
Dr. Faubion also stressed that “menopausal hormone therapy remains the most effective treatment for menopausal symptoms,” and that “women should not be reflexively directed to other pharmacologic therapies for management of menopausal symptoms.”
The distinction the USPSTF makes between its recommendations against using hormone therapy to prevent chronic conditions and its deferral of comment on use of the same treatment to manage perimenopausal symptoms is often forgotten, note Alison J. Huang, MD, and Deborah Grady, MD, in their editorial.
A problem of conflation
“Many patients and clinicians conflate these two different indications,” they write.
The notion that the net harms of menopausal hormone therapy outweigh the benefits “is now widely adopted as a rationale for foregoing menopausal hormone therapy for symptomatic treatment,” even though “nonhormonal treatments that are as effective as menopausal hormone therapy have not yet been identified,” say Dr. Huang and Dr. Grady, both physicians at the University of California, San Francisco.
In addition, alternative, nonhormonal options for treating perimenopausal symptoms have not received the same level of scrutiny as hormonal treatment, they say.
“It is arguably problematic to avoid menopausal hormone therapy and favor potentially less effective treatments, when the longer-term implications of those treatments for health have not been evaluated,” Dr. Huang and Dr. Grady write in their editorial.
In short, during menopause, people are at risk of being “frightened away from considering using menopausal hormone therapy for distressing symptoms,” they say.
“We can’t speak to whether or how often clinicians might be conflating the role of hormone therapy in treating symptoms and preventing chronic conditions,” answered Dr. Mangione.
“We hope to ensure that health professionals know that hormone therapy is not a beneficial way to reduce the risk of chronic conditions such as heart disease, cancer, and strokes,” she added. The new recommendations are an effort to “raise awareness about the value of considering other safe and effective ways for people to reduce their risk of chronic health problems as they age.”
The issue of timing
Another critique offered by Dr. Huang and Dr. Grady in their editorial is that “the scientific and medical community should let go of the past,” and should no longer invest additional resources in “trying to parse out subsets of menopausal patients who may derive some preventive benefit from menopausal hormone therapy for a limited amount of time.”
But Dr. Mangione disagreed.
The USPSTF “calls for more research that can help us understand whether health outcomes – both benefits and harms – differ depending on a person’s age or when they started hormone therapy related to when they went through menopause,” she said.
Dr. Mangione also highlighted the need for additional research on whether the benefits and risks of menopausal hormone therapy vary across racial and ethnic groups.
USPSTF receives no commercial funding. Dr. Mangione, Dr. Huang, and Dr. Grady have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The U.S. Preventive Services Task Force moved forward their recommendations for using hormone therapy to prevent chronic conditions in postmenopausal women by keeping them the same.
The central message of the new recommendations, released on Nov. 1 as a statement published in JAMA, remains unchanged from the last update in 2017.
The message also remains simple: Don’t use hormone therapy for preventing chronic conditions, such as cardiovascular disease, cancer, and osteoporosis, or bone fracture.
The USPSTF summarized its recommendations in two brief statements: the group “recommends against the use of combined estrogen and progestin for the primary prevention of chronic conditions in postmenopausal persons” and “recommends against the use of estrogen alone for the primary prevention of chronic conditions in postmenopausal persons who have had a hysterectomy.”
This wording is identical to that used in the 2017 guidance (except it now refers to postmenopausal persons instead of specifically women). The recommendation against use of estrogen and progestin for prevention of chronic conditions in postmenopausal women was first made by the USPSTF in 2002.
An editorial accompanying the 2022 revision notes that the evidence cited by the USPSTF includes “only two additional, modest-sized trials” (that focused on the effects of hormone therapy on cognition and brain structure) compared with 2017, “as well as ancillary analyses of previous trials.”
A standard 5-year update
The 2022 revision and revisiting of the evidence base by the Task Force regarding the benefits and risks of postmenopausal hormone therapy occurred “as part of the Task Force’s standard approach, which includes updating each recommendation approximately every 5 years,” explained Carol M. Mangione, MD, who is USPSTF chair and chief of the division of general internal medicine and health services research at the University of California, Los Angeles.
“In our review we again found that while hormone therapy may reduce the risk of some conditions, it can also lead to serious harms such as an increase in the risk of blood clots and stroke,” Dr. Mangione said in an interview. “The harms cancel out any potential benefits overall.”
This new statement only applies to using menopausal hormone treatment for preventing chronic conditions in asymptomatic people but does not speak to using this treatment in managing people with perimenopausal symptoms such as hot flashes or vaginal dryness or treating people with premature or surgical menopause, Dr. Mangione highlighted.
No review for treating menopausal symptoms
“The Task Force encourages people who are experiencing symptoms of menopause to talk with their health care professional about the best treatment for them,” explained Dr. Mangione. “The Task Force did not review the evidence on the use of hormone therapy to treat symptoms of menopause.”
Osteoporosis and increased risk for bone fracture were among the conditions that accompany menopause reviewed by the USPSTF. The Task Force concluded that while “hormone therapy was associated with decreased risk of fractures,” after weighing the benefits and harms for preventing this condition, “there is no net benefit at the population level.”
This conclusion seems to contrast with the 2022 hormone therapy position statement of the North American Menopause Society (NAMS), released in July, which states: “For women aged younger than 60 years or who are within 10 years of menopause onset and have no contraindications, the benefit-risk ratio is favorable for treatment of bothersome vasomotor symptoms and prevention of bone loss.”
USPSTF, NAMS are ‘completely consistent’
However, Stephanie S. Faubion, MD, medical director of NAMS and director of the women’s health clinic at Mayo Clinic, Rochester, Minn., said the new USPSTF recommendations “are completely consistent” with the recent NAMS statement.
“We are entirely aligned with the recommendation to use hormone therapy for management of menopausal symptoms and not for chronic disease prevention or as an anti-aging strategy,” Dr. Faubion commented in an interview.
Dr. Faubion also stressed that “menopausal hormone therapy remains the most effective treatment for menopausal symptoms,” and that “women should not be reflexively directed to other pharmacologic therapies for management of menopausal symptoms.”
The distinction the USPSTF makes between its recommendations against using hormone therapy to prevent chronic conditions and its deferral of comment on use of the same treatment to manage perimenopausal symptoms is often forgotten, note Alison J. Huang, MD, and Deborah Grady, MD, in their editorial.
A problem of conflation
“Many patients and clinicians conflate these two different indications,” they write.
The notion that the net harms of menopausal hormone therapy outweigh the benefits “is now widely adopted as a rationale for foregoing menopausal hormone therapy for symptomatic treatment,” even though “nonhormonal treatments that are as effective as menopausal hormone therapy have not yet been identified,” say Dr. Huang and Dr. Grady, both physicians at the University of California, San Francisco.
In addition, alternative, nonhormonal options for treating perimenopausal symptoms have not received the same level of scrutiny as hormonal treatment, they say.
“It is arguably problematic to avoid menopausal hormone therapy and favor potentially less effective treatments, when the longer-term implications of those treatments for health have not been evaluated,” Dr. Huang and Dr. Grady write in their editorial.
In short, during menopause, people are at risk of being “frightened away from considering using menopausal hormone therapy for distressing symptoms,” they say.
“We can’t speak to whether or how often clinicians might be conflating the role of hormone therapy in treating symptoms and preventing chronic conditions,” answered Dr. Mangione.
“We hope to ensure that health professionals know that hormone therapy is not a beneficial way to reduce the risk of chronic conditions such as heart disease, cancer, and strokes,” she added. The new recommendations are an effort to “raise awareness about the value of considering other safe and effective ways for people to reduce their risk of chronic health problems as they age.”
The issue of timing
Another critique offered by Dr. Huang and Dr. Grady in their editorial is that “the scientific and medical community should let go of the past,” and should no longer invest additional resources in “trying to parse out subsets of menopausal patients who may derive some preventive benefit from menopausal hormone therapy for a limited amount of time.”
But Dr. Mangione disagreed.
The USPSTF “calls for more research that can help us understand whether health outcomes – both benefits and harms – differ depending on a person’s age or when they started hormone therapy related to when they went through menopause,” she said.
Dr. Mangione also highlighted the need for additional research on whether the benefits and risks of menopausal hormone therapy vary across racial and ethnic groups.
USPSTF receives no commercial funding. Dr. Mangione, Dr. Huang, and Dr. Grady have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The U.S. Preventive Services Task Force moved forward their recommendations for using hormone therapy to prevent chronic conditions in postmenopausal women by keeping them the same.
The central message of the new recommendations, released on Nov. 1 as a statement published in JAMA, remains unchanged from the last update in 2017.
The message also remains simple: Don’t use hormone therapy for preventing chronic conditions, such as cardiovascular disease, cancer, and osteoporosis, or bone fracture.
The USPSTF summarized its recommendations in two brief statements: the group “recommends against the use of combined estrogen and progestin for the primary prevention of chronic conditions in postmenopausal persons” and “recommends against the use of estrogen alone for the primary prevention of chronic conditions in postmenopausal persons who have had a hysterectomy.”
This wording is identical to that used in the 2017 guidance (except it now refers to postmenopausal persons instead of specifically women). The recommendation against use of estrogen and progestin for prevention of chronic conditions in postmenopausal women was first made by the USPSTF in 2002.
An editorial accompanying the 2022 revision notes that the evidence cited by the USPSTF includes “only two additional, modest-sized trials” (that focused on the effects of hormone therapy on cognition and brain structure) compared with 2017, “as well as ancillary analyses of previous trials.”
A standard 5-year update
The 2022 revision and revisiting of the evidence base by the Task Force regarding the benefits and risks of postmenopausal hormone therapy occurred “as part of the Task Force’s standard approach, which includes updating each recommendation approximately every 5 years,” explained Carol M. Mangione, MD, who is USPSTF chair and chief of the division of general internal medicine and health services research at the University of California, Los Angeles.
“In our review we again found that while hormone therapy may reduce the risk of some conditions, it can also lead to serious harms such as an increase in the risk of blood clots and stroke,” Dr. Mangione said in an interview. “The harms cancel out any potential benefits overall.”
This new statement only applies to using menopausal hormone treatment for preventing chronic conditions in asymptomatic people but does not speak to using this treatment in managing people with perimenopausal symptoms such as hot flashes or vaginal dryness or treating people with premature or surgical menopause, Dr. Mangione highlighted.
No review for treating menopausal symptoms
“The Task Force encourages people who are experiencing symptoms of menopause to talk with their health care professional about the best treatment for them,” explained Dr. Mangione. “The Task Force did not review the evidence on the use of hormone therapy to treat symptoms of menopause.”
Osteoporosis and increased risk for bone fracture were among the conditions that accompany menopause reviewed by the USPSTF. The Task Force concluded that while “hormone therapy was associated with decreased risk of fractures,” after weighing the benefits and harms for preventing this condition, “there is no net benefit at the population level.”
This conclusion seems to contrast with the 2022 hormone therapy position statement of the North American Menopause Society (NAMS), released in July, which states: “For women aged younger than 60 years or who are within 10 years of menopause onset and have no contraindications, the benefit-risk ratio is favorable for treatment of bothersome vasomotor symptoms and prevention of bone loss.”
USPSTF, NAMS are ‘completely consistent’
However, Stephanie S. Faubion, MD, medical director of NAMS and director of the women’s health clinic at Mayo Clinic, Rochester, Minn., said the new USPSTF recommendations “are completely consistent” with the recent NAMS statement.
“We are entirely aligned with the recommendation to use hormone therapy for management of menopausal symptoms and not for chronic disease prevention or as an anti-aging strategy,” Dr. Faubion commented in an interview.
Dr. Faubion also stressed that “menopausal hormone therapy remains the most effective treatment for menopausal symptoms,” and that “women should not be reflexively directed to other pharmacologic therapies for management of menopausal symptoms.”
The distinction the USPSTF makes between its recommendations against using hormone therapy to prevent chronic conditions and its deferral of comment on use of the same treatment to manage perimenopausal symptoms is often forgotten, note Alison J. Huang, MD, and Deborah Grady, MD, in their editorial.
A problem of conflation
“Many patients and clinicians conflate these two different indications,” they write.
The notion that the net harms of menopausal hormone therapy outweigh the benefits “is now widely adopted as a rationale for foregoing menopausal hormone therapy for symptomatic treatment,” even though “nonhormonal treatments that are as effective as menopausal hormone therapy have not yet been identified,” say Dr. Huang and Dr. Grady, both physicians at the University of California, San Francisco.
In addition, alternative, nonhormonal options for treating perimenopausal symptoms have not received the same level of scrutiny as hormonal treatment, they say.
“It is arguably problematic to avoid menopausal hormone therapy and favor potentially less effective treatments, when the longer-term implications of those treatments for health have not been evaluated,” Dr. Huang and Dr. Grady write in their editorial.
In short, during menopause, people are at risk of being “frightened away from considering using menopausal hormone therapy for distressing symptoms,” they say.
“We can’t speak to whether or how often clinicians might be conflating the role of hormone therapy in treating symptoms and preventing chronic conditions,” answered Dr. Mangione.
“We hope to ensure that health professionals know that hormone therapy is not a beneficial way to reduce the risk of chronic conditions such as heart disease, cancer, and strokes,” she added. The new recommendations are an effort to “raise awareness about the value of considering other safe and effective ways for people to reduce their risk of chronic health problems as they age.”
The issue of timing
Another critique offered by Dr. Huang and Dr. Grady in their editorial is that “the scientific and medical community should let go of the past,” and should no longer invest additional resources in “trying to parse out subsets of menopausal patients who may derive some preventive benefit from menopausal hormone therapy for a limited amount of time.”
But Dr. Mangione disagreed.
The USPSTF “calls for more research that can help us understand whether health outcomes – both benefits and harms – differ depending on a person’s age or when they started hormone therapy related to when they went through menopause,” she said.
Dr. Mangione also highlighted the need for additional research on whether the benefits and risks of menopausal hormone therapy vary across racial and ethnic groups.
USPSTF receives no commercial funding. Dr. Mangione, Dr. Huang, and Dr. Grady have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM JAMA
Finerenone: ‘Striking’ cut in pneumonia, COVID-19 risks
The nonsteroidal mineralocorticoid receptor antagonist finerenone (Kerendia) unexpectedly showed that it might protect against incident infective pneumonia and COVID-19. The finding was based on secondary analyses run on more than 13,000 people enrolled in the two pivotal trials for finerenone.
Finerenone was approved by the Food and Drug Administration in 2021 for slowing progressive renal dysfunction and preventing cardiovascular events in adults with type 2 diabetes and chronic kidney disease (CKD).
‘Striking reduction in the risk of pneumonia’
The “striking reduction in risk of pneumonia” in a new analysis suggests that “the propagation of pulmonary infection into lobar or bronchial consolidation may be reduced by finerenone,” write Bertram Pitt, MD, and coauthors in a report published on October 26 in JAMA Network Open.
They also suggest that if further studies confirm that finerenone treatment reduces complications from pneumonia and COVID-19, it would have “significant medical implications,” especially because of the limited treatment options now available for complications from COVID-19.
The new analyses used the FIDELITY dataset, a prespecified merging of results from the FIDELIO-DKD and FIGARO-DKD trials, which together enrolled 13,026 people with type 2 diabetes and CKD, as determined on the basis of the patients’ having a urine albumin-to-creatinine ratio of at least 30 mg/g.
The primary outcomes of these trials showed that treatment with finerenone led to significant slowing of the progression of CKD and a significant reduction in the incidence of cardiovascular events, compared with placebo during median follow-up of 3 years.
The new, secondary analyses focused on the 6.0% of participants in whom there was evidence of pneumonia and the 1.6% in whom there was evidence of having COVID-19. Pneumonia was the most common serious adverse event in the two trials, a finding consistent with the documented risk for pneumonia faced by people with CKD.
Finerenone linked with a 29% relative reduction in pneumonia
When analyzed by treatment, the incidence of pneumonia was 4.7% among those who received finerenone and 6.7% among those who received placebo. This translated into a significant relative risk reduction of 29% associated with finerenone treatment.
Analysis of COVID-19 adverse events showed a 1.3% incidence among those who received finerenone and a 1.8% incidence among those in the placebo group, which translated into a significant 27% relative risk reduction linked with finerenone treatment.
In contrast, the data showed no reduced incidence of several other respiratory infections among the finerenone recipients, including nasopharyngitis, bronchitis, and influenza. The data also showed no signal that pneumonia or COVID-19 was more severe among the people who did not receive finerenone, nor did finerenone treatment appear to affect pneumonia recovery.
Analysis based on adverse events reports
These secondary analyses are far from definitive. The authors relied on pneumonia and COVID-19 being reported as adverse events. Each investigator diagnosed pneumonia at their discretion, and the trials did not specify diagnostic criteria. The authors also acknowledge that testing for COVID-19 was “not widespread” and that one of the two pivotal trials largely ran prior to the onset of the COVID-19 pandemic so that only 6 participants developed COVID-19 symptoms out of more than 5,700 enrolled.
The authors hypothesize that several actions of finerenone might potentially help mediate an effect on pneumonia and COVID-19: improvements in pulmonary inflammation and fibrosis, upregulation of expression of angiotensin converting enzyme 2, and amelioration of right heart pressure and pulmonary congestion. Also, antagonizing the mineralocorticoid receptor on monocytes and macrophages may block macrophage infiltration and accumulation of active macrophages, which can mediate the pulmonary tissue damage caused by COVID-19.
The FIDELIO-DKD and FIGARO-DKD trials and the FIDELITY combined database were sponsored by Bayer, the company that markets finerenone (Kerendia). Dr. Pitt has received personal fees from Bayer and personal fees and stock options from numerous other companies. Several coauthors reported having a financial relationship with Bayer, as well as with other companies.
A version of this article first appeared on Medscape.com.
The nonsteroidal mineralocorticoid receptor antagonist finerenone (Kerendia) unexpectedly showed that it might protect against incident infective pneumonia and COVID-19. The finding was based on secondary analyses run on more than 13,000 people enrolled in the two pivotal trials for finerenone.
Finerenone was approved by the Food and Drug Administration in 2021 for slowing progressive renal dysfunction and preventing cardiovascular events in adults with type 2 diabetes and chronic kidney disease (CKD).
‘Striking reduction in the risk of pneumonia’
The “striking reduction in risk of pneumonia” in a new analysis suggests that “the propagation of pulmonary infection into lobar or bronchial consolidation may be reduced by finerenone,” write Bertram Pitt, MD, and coauthors in a report published on October 26 in JAMA Network Open.
They also suggest that if further studies confirm that finerenone treatment reduces complications from pneumonia and COVID-19, it would have “significant medical implications,” especially because of the limited treatment options now available for complications from COVID-19.
The new analyses used the FIDELITY dataset, a prespecified merging of results from the FIDELIO-DKD and FIGARO-DKD trials, which together enrolled 13,026 people with type 2 diabetes and CKD, as determined on the basis of the patients’ having a urine albumin-to-creatinine ratio of at least 30 mg/g.
The primary outcomes of these trials showed that treatment with finerenone led to significant slowing of the progression of CKD and a significant reduction in the incidence of cardiovascular events, compared with placebo during median follow-up of 3 years.
The new, secondary analyses focused on the 6.0% of participants in whom there was evidence of pneumonia and the 1.6% in whom there was evidence of having COVID-19. Pneumonia was the most common serious adverse event in the two trials, a finding consistent with the documented risk for pneumonia faced by people with CKD.
Finerenone linked with a 29% relative reduction in pneumonia
When analyzed by treatment, the incidence of pneumonia was 4.7% among those who received finerenone and 6.7% among those who received placebo. This translated into a significant relative risk reduction of 29% associated with finerenone treatment.
Analysis of COVID-19 adverse events showed a 1.3% incidence among those who received finerenone and a 1.8% incidence among those in the placebo group, which translated into a significant 27% relative risk reduction linked with finerenone treatment.
In contrast, the data showed no reduced incidence of several other respiratory infections among the finerenone recipients, including nasopharyngitis, bronchitis, and influenza. The data also showed no signal that pneumonia or COVID-19 was more severe among the people who did not receive finerenone, nor did finerenone treatment appear to affect pneumonia recovery.
Analysis based on adverse events reports
These secondary analyses are far from definitive. The authors relied on pneumonia and COVID-19 being reported as adverse events. Each investigator diagnosed pneumonia at their discretion, and the trials did not specify diagnostic criteria. The authors also acknowledge that testing for COVID-19 was “not widespread” and that one of the two pivotal trials largely ran prior to the onset of the COVID-19 pandemic so that only 6 participants developed COVID-19 symptoms out of more than 5,700 enrolled.
The authors hypothesize that several actions of finerenone might potentially help mediate an effect on pneumonia and COVID-19: improvements in pulmonary inflammation and fibrosis, upregulation of expression of angiotensin converting enzyme 2, and amelioration of right heart pressure and pulmonary congestion. Also, antagonizing the mineralocorticoid receptor on monocytes and macrophages may block macrophage infiltration and accumulation of active macrophages, which can mediate the pulmonary tissue damage caused by COVID-19.
The FIDELIO-DKD and FIGARO-DKD trials and the FIDELITY combined database were sponsored by Bayer, the company that markets finerenone (Kerendia). Dr. Pitt has received personal fees from Bayer and personal fees and stock options from numerous other companies. Several coauthors reported having a financial relationship with Bayer, as well as with other companies.
A version of this article first appeared on Medscape.com.
The nonsteroidal mineralocorticoid receptor antagonist finerenone (Kerendia) unexpectedly showed that it might protect against incident infective pneumonia and COVID-19. The finding was based on secondary analyses run on more than 13,000 people enrolled in the two pivotal trials for finerenone.
Finerenone was approved by the Food and Drug Administration in 2021 for slowing progressive renal dysfunction and preventing cardiovascular events in adults with type 2 diabetes and chronic kidney disease (CKD).
‘Striking reduction in the risk of pneumonia’
The “striking reduction in risk of pneumonia” in a new analysis suggests that “the propagation of pulmonary infection into lobar or bronchial consolidation may be reduced by finerenone,” write Bertram Pitt, MD, and coauthors in a report published on October 26 in JAMA Network Open.
They also suggest that if further studies confirm that finerenone treatment reduces complications from pneumonia and COVID-19, it would have “significant medical implications,” especially because of the limited treatment options now available for complications from COVID-19.
The new analyses used the FIDELITY dataset, a prespecified merging of results from the FIDELIO-DKD and FIGARO-DKD trials, which together enrolled 13,026 people with type 2 diabetes and CKD, as determined on the basis of the patients’ having a urine albumin-to-creatinine ratio of at least 30 mg/g.
The primary outcomes of these trials showed that treatment with finerenone led to significant slowing of the progression of CKD and a significant reduction in the incidence of cardiovascular events, compared with placebo during median follow-up of 3 years.
The new, secondary analyses focused on the 6.0% of participants in whom there was evidence of pneumonia and the 1.6% in whom there was evidence of having COVID-19. Pneumonia was the most common serious adverse event in the two trials, a finding consistent with the documented risk for pneumonia faced by people with CKD.
Finerenone linked with a 29% relative reduction in pneumonia
When analyzed by treatment, the incidence of pneumonia was 4.7% among those who received finerenone and 6.7% among those who received placebo. This translated into a significant relative risk reduction of 29% associated with finerenone treatment.
Analysis of COVID-19 adverse events showed a 1.3% incidence among those who received finerenone and a 1.8% incidence among those in the placebo group, which translated into a significant 27% relative risk reduction linked with finerenone treatment.
In contrast, the data showed no reduced incidence of several other respiratory infections among the finerenone recipients, including nasopharyngitis, bronchitis, and influenza. The data also showed no signal that pneumonia or COVID-19 was more severe among the people who did not receive finerenone, nor did finerenone treatment appear to affect pneumonia recovery.
Analysis based on adverse events reports
These secondary analyses are far from definitive. The authors relied on pneumonia and COVID-19 being reported as adverse events. Each investigator diagnosed pneumonia at their discretion, and the trials did not specify diagnostic criteria. The authors also acknowledge that testing for COVID-19 was “not widespread” and that one of the two pivotal trials largely ran prior to the onset of the COVID-19 pandemic so that only 6 participants developed COVID-19 symptoms out of more than 5,700 enrolled.
The authors hypothesize that several actions of finerenone might potentially help mediate an effect on pneumonia and COVID-19: improvements in pulmonary inflammation and fibrosis, upregulation of expression of angiotensin converting enzyme 2, and amelioration of right heart pressure and pulmonary congestion. Also, antagonizing the mineralocorticoid receptor on monocytes and macrophages may block macrophage infiltration and accumulation of active macrophages, which can mediate the pulmonary tissue damage caused by COVID-19.
The FIDELIO-DKD and FIGARO-DKD trials and the FIDELITY combined database were sponsored by Bayer, the company that markets finerenone (Kerendia). Dr. Pitt has received personal fees from Bayer and personal fees and stock options from numerous other companies. Several coauthors reported having a financial relationship with Bayer, as well as with other companies.
A version of this article first appeared on Medscape.com.
‘Too good to be true’? Ultrasound safely treats kidney stones
Treatment with transcutaneous, focused ultrasound safely led to the repositioning and rupture of a majority of stones in the ureter when tested in 29 people at two U.S. centers in the first human feasibility study of the technology.*
potentially relieving pain and facilitating passage in awake patients,” write M. Kennedy Hall, MD, an emergency medicine physician at the University of Washington School of Medicine, Seattle, and co-authors in a report published in the Journal of Urology.
“This is the first human trial in awake subjects” of this method for nonsurgically facilitating ureteral stone clearance, and the results of limited patient discomfort and stone motion in 66% of treated patients seem “almost too good to be true,” comments Karen L. Stern, MD, a urologist at the Mayo Clinic, Phoenix, in an accompanying editorial.
However, Dr. Stern notes two study limitations. First, to correctly target the focused ultrasound clinicians first need to visualize a stone with ultrasound. However, “most urologists are not experienced in ultrasound,” a limitation that could mean the treatment may be more likely performed by emergency physicians or radiologists in the future.
Second, the study had no control patients, and Dr. Stern cautions that the clinical significance of BWL cannot be definitively assessed without a randomized trial that directly compares the new method with either spontaneous stone passage or medical expulsion therapy.
“The authors showed a distal ureteral stone passage [rate] of 81%, but those stones passed within days, not minutes, of the procedure, and that rate is not too far off published data on spontaneous passage,” Dr. Stern notes in her editorial.*
Despite these caveats, Dr. Stern calls the potential for BWL “immense.”
Ultrasound for 10 minutes or less
The study enrolled adults who presented to the University of Washington emergency department or endo-urology clinic with a proximal or distal ureteral stone. Twenty-nine awake, unanesthetized patients in whom clinicians had an unobstructed view of a stone in the focal zone received ultrasound treatment performed by trained personnel.
Treatment involved ultrasound bursts of up to 3 seconds for stone propulsion and 30 seconds at a time for BWL. Total ultrasound exposure could not exceed 10 minutes, and no patient underwent more than one treatment. Sixteen patients received treatment for propulsion only, and 13 received both propulsion and BWL treatments.
The primary outcome was stone motion, which occurred in 19 of the 29 patients (66%). A prespecified secondary outcome was passage of the stone in the 26 patients with distal stones. Among the 21 patients with at least 14 days of follow-up, passage occurred in 18 (86%) after an average of 3.9 days following treatment. The researchers also confirmed stone fragmentation in five of the 13 patients (38%) who received BWL treatment.
The researchers infer that ultrasound treatment facilitated stone passage by stone propulsion, fragmentation, and peristalsis.
Mathew D. Sorensen, MD, a study co-investigator, likened the effect of ultrasound on the stones to a leaf blower on garden debris.
“Essentially, we use the acoustic energy of ultrasound, which gets focused on the stone and creates movement, like a blower,” said Dr. Sorensen, a urologist at the University of Washington School of Medicine. “A push of energy lasts a second or two, sort of a sweeping movement to try to get fragments to move out of what’s usually the bottom of the kidney, toward the exit. Because the energy moves in one way, away from the probe, it’s sort of like playing pool,” he explained.
All 29 treated patients in the current study tolerated the procedure, and none experienced unanticipated events. No patients needed to visit the emergency department or an intervention because of the treatment, and there were no observed ureter injuries.
Pain scores dropped significantly, procedure is ‘nearly painless’
Assessment of pain scores by each patient before and after treatment showed overall significant decreases in both mean and median scores, with 10 patients reporting decreased pain and two reporting increased pain.
When discomfort occurred during the procedure it was described by patients as either similar to a pinprick or as a referred sensation to pass urine and the stone. These effects occurred during 18 of 820 (2%) total propulsive bursts of ultrasound administered.
“It’s nearly painless, and you can do it while the patient is awake, and without sedation, which is critical,” said Dr. Hall in a statement from the University of Washington School of Medicine. He envisions eventually performing the procedure in a clinic or emergency department setting.
All three patients with a proximal stone and three patients with a distal stone who did not pass their stone after treatment underwent surgical stone removal.
The researchers acknowledge that a lack of a control group was a study limitation. They cite a historical, spontaneous stone passage rate of 54% included in a 2016 guideline from the American Urological Association and based on a meta-analysis of 27 studies with 1,205 total patients.
The study was funded by the United States National Aeronautics and Space Administration, which is interested in having a technology available to treat ureteral stones that may develop during prolonged space travel.
The study received no commercial funding. Four of the study’s 23 authors, including Dr. Sorensen, are consultants to and hold equity in SonoMotion, a company that has licensed the tested technology from the University of Washington for commercial development. The report did not identify a specific manufacturer of the ultrasound equipment used for treatment.
A version of this article first appeared on Medscape.com.
*Correction, 10/21/22: An earlier version of this article misstated the location of the stones. They were in the ureter.
Treatment with transcutaneous, focused ultrasound safely led to the repositioning and rupture of a majority of stones in the ureter when tested in 29 people at two U.S. centers in the first human feasibility study of the technology.*
potentially relieving pain and facilitating passage in awake patients,” write M. Kennedy Hall, MD, an emergency medicine physician at the University of Washington School of Medicine, Seattle, and co-authors in a report published in the Journal of Urology.
“This is the first human trial in awake subjects” of this method for nonsurgically facilitating ureteral stone clearance, and the results of limited patient discomfort and stone motion in 66% of treated patients seem “almost too good to be true,” comments Karen L. Stern, MD, a urologist at the Mayo Clinic, Phoenix, in an accompanying editorial.
However, Dr. Stern notes two study limitations. First, to correctly target the focused ultrasound clinicians first need to visualize a stone with ultrasound. However, “most urologists are not experienced in ultrasound,” a limitation that could mean the treatment may be more likely performed by emergency physicians or radiologists in the future.
Second, the study had no control patients, and Dr. Stern cautions that the clinical significance of BWL cannot be definitively assessed without a randomized trial that directly compares the new method with either spontaneous stone passage or medical expulsion therapy.
“The authors showed a distal ureteral stone passage [rate] of 81%, but those stones passed within days, not minutes, of the procedure, and that rate is not too far off published data on spontaneous passage,” Dr. Stern notes in her editorial.*
Despite these caveats, Dr. Stern calls the potential for BWL “immense.”
Ultrasound for 10 minutes or less
The study enrolled adults who presented to the University of Washington emergency department or endo-urology clinic with a proximal or distal ureteral stone. Twenty-nine awake, unanesthetized patients in whom clinicians had an unobstructed view of a stone in the focal zone received ultrasound treatment performed by trained personnel.
Treatment involved ultrasound bursts of up to 3 seconds for stone propulsion and 30 seconds at a time for BWL. Total ultrasound exposure could not exceed 10 minutes, and no patient underwent more than one treatment. Sixteen patients received treatment for propulsion only, and 13 received both propulsion and BWL treatments.
The primary outcome was stone motion, which occurred in 19 of the 29 patients (66%). A prespecified secondary outcome was passage of the stone in the 26 patients with distal stones. Among the 21 patients with at least 14 days of follow-up, passage occurred in 18 (86%) after an average of 3.9 days following treatment. The researchers also confirmed stone fragmentation in five of the 13 patients (38%) who received BWL treatment.
The researchers infer that ultrasound treatment facilitated stone passage by stone propulsion, fragmentation, and peristalsis.
Mathew D. Sorensen, MD, a study co-investigator, likened the effect of ultrasound on the stones to a leaf blower on garden debris.
“Essentially, we use the acoustic energy of ultrasound, which gets focused on the stone and creates movement, like a blower,” said Dr. Sorensen, a urologist at the University of Washington School of Medicine. “A push of energy lasts a second or two, sort of a sweeping movement to try to get fragments to move out of what’s usually the bottom of the kidney, toward the exit. Because the energy moves in one way, away from the probe, it’s sort of like playing pool,” he explained.
All 29 treated patients in the current study tolerated the procedure, and none experienced unanticipated events. No patients needed to visit the emergency department or an intervention because of the treatment, and there were no observed ureter injuries.
Pain scores dropped significantly, procedure is ‘nearly painless’
Assessment of pain scores by each patient before and after treatment showed overall significant decreases in both mean and median scores, with 10 patients reporting decreased pain and two reporting increased pain.
When discomfort occurred during the procedure it was described by patients as either similar to a pinprick or as a referred sensation to pass urine and the stone. These effects occurred during 18 of 820 (2%) total propulsive bursts of ultrasound administered.
“It’s nearly painless, and you can do it while the patient is awake, and without sedation, which is critical,” said Dr. Hall in a statement from the University of Washington School of Medicine. He envisions eventually performing the procedure in a clinic or emergency department setting.
All three patients with a proximal stone and three patients with a distal stone who did not pass their stone after treatment underwent surgical stone removal.
The researchers acknowledge that a lack of a control group was a study limitation. They cite a historical, spontaneous stone passage rate of 54% included in a 2016 guideline from the American Urological Association and based on a meta-analysis of 27 studies with 1,205 total patients.
The study was funded by the United States National Aeronautics and Space Administration, which is interested in having a technology available to treat ureteral stones that may develop during prolonged space travel.
The study received no commercial funding. Four of the study’s 23 authors, including Dr. Sorensen, are consultants to and hold equity in SonoMotion, a company that has licensed the tested technology from the University of Washington for commercial development. The report did not identify a specific manufacturer of the ultrasound equipment used for treatment.
A version of this article first appeared on Medscape.com.
*Correction, 10/21/22: An earlier version of this article misstated the location of the stones. They were in the ureter.
Treatment with transcutaneous, focused ultrasound safely led to the repositioning and rupture of a majority of stones in the ureter when tested in 29 people at two U.S. centers in the first human feasibility study of the technology.*
potentially relieving pain and facilitating passage in awake patients,” write M. Kennedy Hall, MD, an emergency medicine physician at the University of Washington School of Medicine, Seattle, and co-authors in a report published in the Journal of Urology.
“This is the first human trial in awake subjects” of this method for nonsurgically facilitating ureteral stone clearance, and the results of limited patient discomfort and stone motion in 66% of treated patients seem “almost too good to be true,” comments Karen L. Stern, MD, a urologist at the Mayo Clinic, Phoenix, in an accompanying editorial.
However, Dr. Stern notes two study limitations. First, to correctly target the focused ultrasound clinicians first need to visualize a stone with ultrasound. However, “most urologists are not experienced in ultrasound,” a limitation that could mean the treatment may be more likely performed by emergency physicians or radiologists in the future.
Second, the study had no control patients, and Dr. Stern cautions that the clinical significance of BWL cannot be definitively assessed without a randomized trial that directly compares the new method with either spontaneous stone passage or medical expulsion therapy.
“The authors showed a distal ureteral stone passage [rate] of 81%, but those stones passed within days, not minutes, of the procedure, and that rate is not too far off published data on spontaneous passage,” Dr. Stern notes in her editorial.*
Despite these caveats, Dr. Stern calls the potential for BWL “immense.”
Ultrasound for 10 minutes or less
The study enrolled adults who presented to the University of Washington emergency department or endo-urology clinic with a proximal or distal ureteral stone. Twenty-nine awake, unanesthetized patients in whom clinicians had an unobstructed view of a stone in the focal zone received ultrasound treatment performed by trained personnel.
Treatment involved ultrasound bursts of up to 3 seconds for stone propulsion and 30 seconds at a time for BWL. Total ultrasound exposure could not exceed 10 minutes, and no patient underwent more than one treatment. Sixteen patients received treatment for propulsion only, and 13 received both propulsion and BWL treatments.
The primary outcome was stone motion, which occurred in 19 of the 29 patients (66%). A prespecified secondary outcome was passage of the stone in the 26 patients with distal stones. Among the 21 patients with at least 14 days of follow-up, passage occurred in 18 (86%) after an average of 3.9 days following treatment. The researchers also confirmed stone fragmentation in five of the 13 patients (38%) who received BWL treatment.
The researchers infer that ultrasound treatment facilitated stone passage by stone propulsion, fragmentation, and peristalsis.
Mathew D. Sorensen, MD, a study co-investigator, likened the effect of ultrasound on the stones to a leaf blower on garden debris.
“Essentially, we use the acoustic energy of ultrasound, which gets focused on the stone and creates movement, like a blower,” said Dr. Sorensen, a urologist at the University of Washington School of Medicine. “A push of energy lasts a second or two, sort of a sweeping movement to try to get fragments to move out of what’s usually the bottom of the kidney, toward the exit. Because the energy moves in one way, away from the probe, it’s sort of like playing pool,” he explained.
All 29 treated patients in the current study tolerated the procedure, and none experienced unanticipated events. No patients needed to visit the emergency department or an intervention because of the treatment, and there were no observed ureter injuries.
Pain scores dropped significantly, procedure is ‘nearly painless’
Assessment of pain scores by each patient before and after treatment showed overall significant decreases in both mean and median scores, with 10 patients reporting decreased pain and two reporting increased pain.
When discomfort occurred during the procedure it was described by patients as either similar to a pinprick or as a referred sensation to pass urine and the stone. These effects occurred during 18 of 820 (2%) total propulsive bursts of ultrasound administered.
“It’s nearly painless, and you can do it while the patient is awake, and without sedation, which is critical,” said Dr. Hall in a statement from the University of Washington School of Medicine. He envisions eventually performing the procedure in a clinic or emergency department setting.
All three patients with a proximal stone and three patients with a distal stone who did not pass their stone after treatment underwent surgical stone removal.
The researchers acknowledge that a lack of a control group was a study limitation. They cite a historical, spontaneous stone passage rate of 54% included in a 2016 guideline from the American Urological Association and based on a meta-analysis of 27 studies with 1,205 total patients.
The study was funded by the United States National Aeronautics and Space Administration, which is interested in having a technology available to treat ureteral stones that may develop during prolonged space travel.
The study received no commercial funding. Four of the study’s 23 authors, including Dr. Sorensen, are consultants to and hold equity in SonoMotion, a company that has licensed the tested technology from the University of Washington for commercial development. The report did not identify a specific manufacturer of the ultrasound equipment used for treatment.
A version of this article first appeared on Medscape.com.
*Correction, 10/21/22: An earlier version of this article misstated the location of the stones. They were in the ureter.
FROM THE JOURNAL OF UROLOGY
Finerenone benefits T2D across spectrum of renal function
Treatment with finerenone produced roughly similar reductions in heart failure–related outcomes in people with type 2 diabetes and chronic kidney disease (CKD) across the spectrum of kidney function, compared with placebo, including those who had albuminuria but a preserved estimated glomerular filtration rate (eGFR), in a post hoc analysis of pooled data from more than 13,000 people.
The findings, from the two pivotal trials for the agent, “reinforce the importance of routine eGFR and UACR [urinary albumin-to-creatinine ratio] screening” in people with type 2 diabetes to identify new candidates for treatment with finerenone (Kerendia), Gerasimos Filippatos, MD, and coauthors said in a report published online in JACC: Heart Failure.
Among the 13,026 patients in the two combined trials, 40% had a preserved eGFR of greater than 60 mL/min per 1.73 m2 despite also having albuminuria with a UACR of at least 30 mg/g, showing how often this combination occurs. But many clinicians “do not follow the guidelines” and fail to measure the UACR in these patients in routine practice, noted Dr. Filippatos at the annual congress of the European Society of Cardiology in August.
“We now have something to do for these patients,” treat them with finerenone, said Dr. Filippatos, professor and director of heart failure at the Attikon University Hospital, Athens.
The availability of finerenone following its U.S. approval in 2021 means clinicians “must get used to measuring UACR” in people with type 2 diabetes even when their eGFR is normal, especially people with type 2 diabetes plus high cardiovascular disease risk, he said.
The Food and Drug Administration approved finerenone, a nonsteroidal mineralocorticoid receptor antagonist, for treating people with type 2 diabetes and CKD in July 2021, but its uptake has been slow, experts say. In a talk in September 2022 during the annual meeting of the European Association for the Study of Diabetes, Jennifer B. Green, MD, estimated that U.S. uptake of finerenone for appropriate people with type 2 diabetes had not advanced beyond 10%.
A recent review also noted that uptake of screening for elevated UACR in U.S. patients with type 2 diabetes was in the range of 10%-40% during 2017-2019, a “shockingly low rate,” said Dr. Green, a professor and diabetes specialist at Duke University, Durham, N.C.
A new reason to screen for albuminuria
“It’s an extremely important message,” Johann Bauersachs, MD, commented in an interview. Results from “many studies have shown that albuminuria is an excellent additional marker for cardiovascular disease risk. But measurement of albuminuria is not widely done, despite guidelines that recommend annual albuminuria testing in people with type 2 diabetes,” said Dr. Bauersachs, professor and head of the department of cardiology at Hannover (Germany) Medical School.
“Even before there was finerenone, there were reasons to measure UACR, but I hope adding finerenone will help, and more clinicians will incorporate UACR into their routine practice,” said Dr. Bauersachs, who was not involved with the finerenone studies.
The analyses reported by Dr. Filippatos and coauthors used data from two related trials of finerenone, FIDELIO-DKD and FIGARO-DKD, combined by prespecified design into a single dataset, FIDELITY, with a total of 13,026 participants eligible for analysis and followed for a median of 3 years. All had type 2 diabetes and CKD based on having a UACR of at least 30 mg/g. Their eGFR levels could run as high as 74 mL/min per 1.73 m2 in FIDELIO-DKD, and as high as 90 mL/min/1.73m2 in FIGARO-DKD. The two trials excluded people with heart failure with reduced ejection fraction, and those with a serum potassium greater than 4.8 mmol/L.
In the FIDELITY dataset treatment with finerenone led to a significant 17% reduction in the combined incidence of cardiovascular death or first hospitalization for heart failure relative to those who received placebo. This relative risk reduction was not affected by either eGFR or UACR values at baseline, the new analysis showed.
The analysis also demonstrated a nonsignificant trend toward greater reductions in heart failure–related outcomes among study participants who began with an eGFR in the normal range of at least 60 mL/min per 1.73 m2. The researchers also found a nonsignificant trend to a greater reduction in heart failure–related events among those with a UACR of less than 300 mg/g.
Finerenone favors patients with less advanced CKD
In short “the magnitude of the treatment benefit tended to favor patients with less advanced CKD,” concluded the researchers, suggesting that “earlier intervention [with finerenone] in the CKD course is likely to provide the greatest long-term benefit on heart failure–related outcomes.” This led them to further infer “the importance of not only routine assessing eGFR, but also perhaps more importantly, routinely screening for UACR to facilitate early diagnosis and early intervention in patients with type 2 diabetes.”
Findings from FIDELIO-DKD and FIGARO-DKD led to recent guideline additions for finerenone by several medical groups. In August 2022, the American Association of Clinical Endocrinologists released an update to its guideline for managing people with diabetes that recommended treating people with type 2 diabetes with finerenone when they have a UACR of at least 30 mg/g if they are already treated with a maximum-tolerated dose of a renin-angiotensin system inhibitor, have a normal serum potassium level, and have an eGFR of at least 25 mL/min per 1.73 m2. The identical recommendation also appeared in a Consensus Report from the American Diabetes Association and KDIGO, an international organization promoting evidence-based management of patients with CKD.
“Finerenone provides a very important contribution because it improves prognosis even in very well managed patients” with type 2 diabetes, commented Lars Rydén, MD, professor of cardiology at the Karolinska Institute in Stockholm, as designated discussant for the report by Dr. Filippatos at the ESC congress.
The findings from the FIDELITY analysis are “trustworthy, and clinically important,” Dr. Rydén said. When left untreated, diabetic kidney disease “reduces life expectancy by an average of 16 years.”
The finerenone trials were sponsored by Bayer, which markets finerenone (Kerendia). Dr. Filippatos has received lecture fees from Bayer as well as from Amgen, Medtronic, Novartis, Servier, and Vifor. Dr. Green has financial ties to Bayer as well as to Anji, AstraZeneca, Boehringer Ingelheim/Lilly, Hawthorne Effect/Omada, Merck, Novo Nordisk, Pfizer, Roche, Sanofi/Lexicon, and Valo. Dr. Bauersachs has been a consultant to Bayer as well as to Amgen, AstraZeneca, Boehringer Ingelheim, Cardior, Cervia, CVRx, Novartis, Pfizer, and Vifor, and he has received research funding from Abiomed. Dr. Rydén has financial ties to Bayer, Boehringer Ingelheim, Eli Lilly, and Novo Nordisk.
Treatment with finerenone produced roughly similar reductions in heart failure–related outcomes in people with type 2 diabetes and chronic kidney disease (CKD) across the spectrum of kidney function, compared with placebo, including those who had albuminuria but a preserved estimated glomerular filtration rate (eGFR), in a post hoc analysis of pooled data from more than 13,000 people.
The findings, from the two pivotal trials for the agent, “reinforce the importance of routine eGFR and UACR [urinary albumin-to-creatinine ratio] screening” in people with type 2 diabetes to identify new candidates for treatment with finerenone (Kerendia), Gerasimos Filippatos, MD, and coauthors said in a report published online in JACC: Heart Failure.
Among the 13,026 patients in the two combined trials, 40% had a preserved eGFR of greater than 60 mL/min per 1.73 m2 despite also having albuminuria with a UACR of at least 30 mg/g, showing how often this combination occurs. But many clinicians “do not follow the guidelines” and fail to measure the UACR in these patients in routine practice, noted Dr. Filippatos at the annual congress of the European Society of Cardiology in August.
“We now have something to do for these patients,” treat them with finerenone, said Dr. Filippatos, professor and director of heart failure at the Attikon University Hospital, Athens.
The availability of finerenone following its U.S. approval in 2021 means clinicians “must get used to measuring UACR” in people with type 2 diabetes even when their eGFR is normal, especially people with type 2 diabetes plus high cardiovascular disease risk, he said.
The Food and Drug Administration approved finerenone, a nonsteroidal mineralocorticoid receptor antagonist, for treating people with type 2 diabetes and CKD in July 2021, but its uptake has been slow, experts say. In a talk in September 2022 during the annual meeting of the European Association for the Study of Diabetes, Jennifer B. Green, MD, estimated that U.S. uptake of finerenone for appropriate people with type 2 diabetes had not advanced beyond 10%.
A recent review also noted that uptake of screening for elevated UACR in U.S. patients with type 2 diabetes was in the range of 10%-40% during 2017-2019, a “shockingly low rate,” said Dr. Green, a professor and diabetes specialist at Duke University, Durham, N.C.
A new reason to screen for albuminuria
“It’s an extremely important message,” Johann Bauersachs, MD, commented in an interview. Results from “many studies have shown that albuminuria is an excellent additional marker for cardiovascular disease risk. But measurement of albuminuria is not widely done, despite guidelines that recommend annual albuminuria testing in people with type 2 diabetes,” said Dr. Bauersachs, professor and head of the department of cardiology at Hannover (Germany) Medical School.
“Even before there was finerenone, there were reasons to measure UACR, but I hope adding finerenone will help, and more clinicians will incorporate UACR into their routine practice,” said Dr. Bauersachs, who was not involved with the finerenone studies.
The analyses reported by Dr. Filippatos and coauthors used data from two related trials of finerenone, FIDELIO-DKD and FIGARO-DKD, combined by prespecified design into a single dataset, FIDELITY, with a total of 13,026 participants eligible for analysis and followed for a median of 3 years. All had type 2 diabetes and CKD based on having a UACR of at least 30 mg/g. Their eGFR levels could run as high as 74 mL/min per 1.73 m2 in FIDELIO-DKD, and as high as 90 mL/min/1.73m2 in FIGARO-DKD. The two trials excluded people with heart failure with reduced ejection fraction, and those with a serum potassium greater than 4.8 mmol/L.
In the FIDELITY dataset treatment with finerenone led to a significant 17% reduction in the combined incidence of cardiovascular death or first hospitalization for heart failure relative to those who received placebo. This relative risk reduction was not affected by either eGFR or UACR values at baseline, the new analysis showed.
The analysis also demonstrated a nonsignificant trend toward greater reductions in heart failure–related outcomes among study participants who began with an eGFR in the normal range of at least 60 mL/min per 1.73 m2. The researchers also found a nonsignificant trend to a greater reduction in heart failure–related events among those with a UACR of less than 300 mg/g.
Finerenone favors patients with less advanced CKD
In short “the magnitude of the treatment benefit tended to favor patients with less advanced CKD,” concluded the researchers, suggesting that “earlier intervention [with finerenone] in the CKD course is likely to provide the greatest long-term benefit on heart failure–related outcomes.” This led them to further infer “the importance of not only routine assessing eGFR, but also perhaps more importantly, routinely screening for UACR to facilitate early diagnosis and early intervention in patients with type 2 diabetes.”
Findings from FIDELIO-DKD and FIGARO-DKD led to recent guideline additions for finerenone by several medical groups. In August 2022, the American Association of Clinical Endocrinologists released an update to its guideline for managing people with diabetes that recommended treating people with type 2 diabetes with finerenone when they have a UACR of at least 30 mg/g if they are already treated with a maximum-tolerated dose of a renin-angiotensin system inhibitor, have a normal serum potassium level, and have an eGFR of at least 25 mL/min per 1.73 m2. The identical recommendation also appeared in a Consensus Report from the American Diabetes Association and KDIGO, an international organization promoting evidence-based management of patients with CKD.
“Finerenone provides a very important contribution because it improves prognosis even in very well managed patients” with type 2 diabetes, commented Lars Rydén, MD, professor of cardiology at the Karolinska Institute in Stockholm, as designated discussant for the report by Dr. Filippatos at the ESC congress.
The findings from the FIDELITY analysis are “trustworthy, and clinically important,” Dr. Rydén said. When left untreated, diabetic kidney disease “reduces life expectancy by an average of 16 years.”
The finerenone trials were sponsored by Bayer, which markets finerenone (Kerendia). Dr. Filippatos has received lecture fees from Bayer as well as from Amgen, Medtronic, Novartis, Servier, and Vifor. Dr. Green has financial ties to Bayer as well as to Anji, AstraZeneca, Boehringer Ingelheim/Lilly, Hawthorne Effect/Omada, Merck, Novo Nordisk, Pfizer, Roche, Sanofi/Lexicon, and Valo. Dr. Bauersachs has been a consultant to Bayer as well as to Amgen, AstraZeneca, Boehringer Ingelheim, Cardior, Cervia, CVRx, Novartis, Pfizer, and Vifor, and he has received research funding from Abiomed. Dr. Rydén has financial ties to Bayer, Boehringer Ingelheim, Eli Lilly, and Novo Nordisk.
Treatment with finerenone produced roughly similar reductions in heart failure–related outcomes in people with type 2 diabetes and chronic kidney disease (CKD) across the spectrum of kidney function, compared with placebo, including those who had albuminuria but a preserved estimated glomerular filtration rate (eGFR), in a post hoc analysis of pooled data from more than 13,000 people.
The findings, from the two pivotal trials for the agent, “reinforce the importance of routine eGFR and UACR [urinary albumin-to-creatinine ratio] screening” in people with type 2 diabetes to identify new candidates for treatment with finerenone (Kerendia), Gerasimos Filippatos, MD, and coauthors said in a report published online in JACC: Heart Failure.
Among the 13,026 patients in the two combined trials, 40% had a preserved eGFR of greater than 60 mL/min per 1.73 m2 despite also having albuminuria with a UACR of at least 30 mg/g, showing how often this combination occurs. But many clinicians “do not follow the guidelines” and fail to measure the UACR in these patients in routine practice, noted Dr. Filippatos at the annual congress of the European Society of Cardiology in August.
“We now have something to do for these patients,” treat them with finerenone, said Dr. Filippatos, professor and director of heart failure at the Attikon University Hospital, Athens.
The availability of finerenone following its U.S. approval in 2021 means clinicians “must get used to measuring UACR” in people with type 2 diabetes even when their eGFR is normal, especially people with type 2 diabetes plus high cardiovascular disease risk, he said.
The Food and Drug Administration approved finerenone, a nonsteroidal mineralocorticoid receptor antagonist, for treating people with type 2 diabetes and CKD in July 2021, but its uptake has been slow, experts say. In a talk in September 2022 during the annual meeting of the European Association for the Study of Diabetes, Jennifer B. Green, MD, estimated that U.S. uptake of finerenone for appropriate people with type 2 diabetes had not advanced beyond 10%.
A recent review also noted that uptake of screening for elevated UACR in U.S. patients with type 2 diabetes was in the range of 10%-40% during 2017-2019, a “shockingly low rate,” said Dr. Green, a professor and diabetes specialist at Duke University, Durham, N.C.
A new reason to screen for albuminuria
“It’s an extremely important message,” Johann Bauersachs, MD, commented in an interview. Results from “many studies have shown that albuminuria is an excellent additional marker for cardiovascular disease risk. But measurement of albuminuria is not widely done, despite guidelines that recommend annual albuminuria testing in people with type 2 diabetes,” said Dr. Bauersachs, professor and head of the department of cardiology at Hannover (Germany) Medical School.
“Even before there was finerenone, there were reasons to measure UACR, but I hope adding finerenone will help, and more clinicians will incorporate UACR into their routine practice,” said Dr. Bauersachs, who was not involved with the finerenone studies.
The analyses reported by Dr. Filippatos and coauthors used data from two related trials of finerenone, FIDELIO-DKD and FIGARO-DKD, combined by prespecified design into a single dataset, FIDELITY, with a total of 13,026 participants eligible for analysis and followed for a median of 3 years. All had type 2 diabetes and CKD based on having a UACR of at least 30 mg/g. Their eGFR levels could run as high as 74 mL/min per 1.73 m2 in FIDELIO-DKD, and as high as 90 mL/min/1.73m2 in FIGARO-DKD. The two trials excluded people with heart failure with reduced ejection fraction, and those with a serum potassium greater than 4.8 mmol/L.
In the FIDELITY dataset treatment with finerenone led to a significant 17% reduction in the combined incidence of cardiovascular death or first hospitalization for heart failure relative to those who received placebo. This relative risk reduction was not affected by either eGFR or UACR values at baseline, the new analysis showed.
The analysis also demonstrated a nonsignificant trend toward greater reductions in heart failure–related outcomes among study participants who began with an eGFR in the normal range of at least 60 mL/min per 1.73 m2. The researchers also found a nonsignificant trend to a greater reduction in heart failure–related events among those with a UACR of less than 300 mg/g.
Finerenone favors patients with less advanced CKD
In short “the magnitude of the treatment benefit tended to favor patients with less advanced CKD,” concluded the researchers, suggesting that “earlier intervention [with finerenone] in the CKD course is likely to provide the greatest long-term benefit on heart failure–related outcomes.” This led them to further infer “the importance of not only routine assessing eGFR, but also perhaps more importantly, routinely screening for UACR to facilitate early diagnosis and early intervention in patients with type 2 diabetes.”
Findings from FIDELIO-DKD and FIGARO-DKD led to recent guideline additions for finerenone by several medical groups. In August 2022, the American Association of Clinical Endocrinologists released an update to its guideline for managing people with diabetes that recommended treating people with type 2 diabetes with finerenone when they have a UACR of at least 30 mg/g if they are already treated with a maximum-tolerated dose of a renin-angiotensin system inhibitor, have a normal serum potassium level, and have an eGFR of at least 25 mL/min per 1.73 m2. The identical recommendation also appeared in a Consensus Report from the American Diabetes Association and KDIGO, an international organization promoting evidence-based management of patients with CKD.
“Finerenone provides a very important contribution because it improves prognosis even in very well managed patients” with type 2 diabetes, commented Lars Rydén, MD, professor of cardiology at the Karolinska Institute in Stockholm, as designated discussant for the report by Dr. Filippatos at the ESC congress.
The findings from the FIDELITY analysis are “trustworthy, and clinically important,” Dr. Rydén said. When left untreated, diabetic kidney disease “reduces life expectancy by an average of 16 years.”
The finerenone trials were sponsored by Bayer, which markets finerenone (Kerendia). Dr. Filippatos has received lecture fees from Bayer as well as from Amgen, Medtronic, Novartis, Servier, and Vifor. Dr. Green has financial ties to Bayer as well as to Anji, AstraZeneca, Boehringer Ingelheim/Lilly, Hawthorne Effect/Omada, Merck, Novo Nordisk, Pfizer, Roche, Sanofi/Lexicon, and Valo. Dr. Bauersachs has been a consultant to Bayer as well as to Amgen, AstraZeneca, Boehringer Ingelheim, Cardior, Cervia, CVRx, Novartis, Pfizer, and Vifor, and he has received research funding from Abiomed. Dr. Rydén has financial ties to Bayer, Boehringer Ingelheim, Eli Lilly, and Novo Nordisk.
FROM JACC: HEART FAILURE
Tirzepatide’s benefits expand: Lean mass up, serum lipids down
STOCKHOLM – New insights into the benefits of treatment with the “twincretin” tirzepatide for people with overweight or obesity – with or without diabetes – come from new findings reported at the annual meeting of the European Association for the Study of Diabetes.
Additional results from the SURMOUNT-1 trial, which matched tirzepatide against placebo in people with overweight or obesity, provide further details on the favorable changes produced by 72 weeks of tirzepatide treatment on outcomes that included fat and lean mass, insulin sensitivity, and patient-reported outcomes related to functional health and well being, reported Ania M. Jastreboff, MD, PhD.
And results from a meta-analysis of six trials that compared tirzepatide (Mounjaro) against several different comparators in patients with type 2 diabetes further confirm the drug’s ability to reliably produce positive changes in blood lipids, especially by significantly lowering levels of triglycerides, LDL cholesterol, and very LDL (VLDL) cholesterol, said Thomas Karagiannis, MD, PhD, in a separate report at the meeting.
Tirzepatide works as an agonist on receptors for both the glucagonlike peptide–1 (GLP-1), and for the glucose-dependent insulinotropic polypeptide, and received Food and Drug Administration approval for treating people with type 2 diabetes in May 2022. On the basis of results from SURMOUNT-1, the FDA on Oct. 6 granted tirzepatide fast-track designation for a proposed labeling of the agent for treating people with overweight or obesity. This FDA decision will likely remain pending at least until results from a second trial in people with overweight or obesity but without diabetes, SURMOUNT-2, become available in 2023.
SURMOUNT-1 randomized 2,539 people with obesity or overweight and at least one weight-related complication to a weekly injection of tirzepatide or placebo for 72 weeks. The study’s primary efficacy endpoints were the average reduction in weight from baseline, and the percentage of people in each treatment arm achieving weight loss of at least 5% from baseline.
For both endpoints, the outcomes with tirzepatide significantly surpassed placebo effects. Average weight loss ranged from 15%-21% from baseline, depending on dose, compared with 3% on placebo. The rate of participants with at least a 5% weight loss ranged from 85% to 91%, compared with 35% with placebo, as reported in July 2022 in the New England Journal of Medicine.
Cutting fat mass, boosting lean mass
New results from the trial reported by Dr. Jastreboff included a cut in fat mass from 46.2% of total body mass at baseline to 38.5% after 72 weeks, compared with a change from 46.8% at baseline to 44.7% after 72 weeks in the placebo group. Concurrently, lean mass increased with tirzepatide treatment from 51.0% at baseline to 58.1% after 72 weeks.
Participants who received tirzepatide, compared with those who received placebo, had “proportionately greater decrease in fat mass and proportionately greater increase in lean mass” compared with those who received placebo, said Dr. Jastreboff, an endocrinologist and obesity medicine specialist with Yale Medicine in New Haven, Conn. “I was impressed by the amount of visceral fat lost.”
These effects translated into a significant reduction in fat mass-to-lean mass ratio among the people treated with tirzepatide, with the greatest reduction in those who lost at least 15% of their starting weight. In that subgroup the fat-to-lean mass ratio dropped from 0.94 at baseline to 0.64 after 72 weeks of treatment, she said.
Focus on diet quality
People treated with tirzepatide “eat so little food that we need to improve the quality of what they eat to protect their muscle,” commented Carel le Roux, MBChB, PhD, a professor in the Diabetes Complications Research Centre of University College Dublin. “You no longer need a dietitian to help people lose weight, because the drug does that. You need dietitians to look after the nutritional health of patients while they lose weight,” Dr. le Roux said in a separate session at the meeting.
Additional tests showed that blood glucose and insulin levels were all significantly lower among trial participants on all three doses of tirzepatide compared with those on placebo, and the tirzepatide-treated subjects also had significant, roughly twofold elevations in their insulin sensitivity measured by the Matsuda Index.
The impact of tirzepatide on glucose and insulin levels and on insulin sensitivity was similar regardless of whether study participants had normoglycemia or prediabetes at entry. By design, no study participants had diabetes.
The trial assessed patient-reported quality-of-life outcomes using the 36-Item Short Form Survey (SF-36). Participants had significant increases in all eight domains within the SF-36 at all three tirzepatide doses, compared with placebo, at 72 weeks, Dr. Jastreboff reported. Improvements in the physical function domain increased most notably among study participants on tirzepatide who had functional limitations at baseline. Heart rate rose among participants who received either of the two highest tirzepatide doses by 2.3-2.5 beats/min, comparable with the effect of other injected incretin-based treatments.
Lipids improve in those with type 2 diabetes
Tirzepatide treatment also results in a “secondary effect” of improving levels of several lipids in people with type 2 diabetes, according to a meta-analysis of findings from six randomized trials. The meta-analysis collectively involved 4,502 participants treated for numerous weeks with one of three doses of tirzepatide and 2,144 people in comparator groups, reported Dr. Karagiannis, a diabetes researcher at Aristotle University of Thessaloniki (Greece).
Among the significant lipid changes linked with tirzepatide treatment, compared with placebo, were an average 13 mg/dL decrease in LDL cholesterol, an average 6 mg/dL decrease in VLDL cholesterol, and an average 50 mg/dL decrease in triglycerides. In comparison to a GLP-1 receptor agonist, an average 25 mg/dL decrease in triglycerides and an average 4 mg/dL reduction in VLDL cholesterol were seen. And trials comparing tirzepatide with basal insulin saw average reductions of 7% in LDL cholesterol, 15% in VLDL cholesterol, 15% in triglycerides, and an 8% increase in HDL cholesterol.
Dr. Karagiannis highlighted that the clinical impact of these effects is unclear, although he noted that the average reduction in LDL cholesterol relative to placebo is of a magnitude that could have a modest effect on long-term outcomes.
These lipid effects of tirzepatide “should be considered alongside” tirzepatide’s “key metabolic effects” on weight and hemoglobin A1c as well as the drug’s safety, concluded Dr. Karagiannis.
The tirzepatide trials were all funded by Eli Lilly, which markets tirzepatide (Mounjaro). Dr. Jastreboff has been an adviser and consultant to Eli Lilly, as well as to Intellihealth, Novo Nordisk, Pfizer, Rhythm Scholars, Roche, and Weight Watchers, and she has received research funding from Eli Lilly and Novo Nordisk. Dr. Karagiannis had no disclosures. Dr. le Roux has had financial relationships with Eli Lilly, as well as with Boehringer Ingelheim, Consilient Health, Covidion, Fractyl, GL Dynamics, Herbalife, Johnson & Johnson, Keyron, and Novo Nordisk.
STOCKHOLM – New insights into the benefits of treatment with the “twincretin” tirzepatide for people with overweight or obesity – with or without diabetes – come from new findings reported at the annual meeting of the European Association for the Study of Diabetes.
Additional results from the SURMOUNT-1 trial, which matched tirzepatide against placebo in people with overweight or obesity, provide further details on the favorable changes produced by 72 weeks of tirzepatide treatment on outcomes that included fat and lean mass, insulin sensitivity, and patient-reported outcomes related to functional health and well being, reported Ania M. Jastreboff, MD, PhD.
And results from a meta-analysis of six trials that compared tirzepatide (Mounjaro) against several different comparators in patients with type 2 diabetes further confirm the drug’s ability to reliably produce positive changes in blood lipids, especially by significantly lowering levels of triglycerides, LDL cholesterol, and very LDL (VLDL) cholesterol, said Thomas Karagiannis, MD, PhD, in a separate report at the meeting.
Tirzepatide works as an agonist on receptors for both the glucagonlike peptide–1 (GLP-1), and for the glucose-dependent insulinotropic polypeptide, and received Food and Drug Administration approval for treating people with type 2 diabetes in May 2022. On the basis of results from SURMOUNT-1, the FDA on Oct. 6 granted tirzepatide fast-track designation for a proposed labeling of the agent for treating people with overweight or obesity. This FDA decision will likely remain pending at least until results from a second trial in people with overweight or obesity but without diabetes, SURMOUNT-2, become available in 2023.
SURMOUNT-1 randomized 2,539 people with obesity or overweight and at least one weight-related complication to a weekly injection of tirzepatide or placebo for 72 weeks. The study’s primary efficacy endpoints were the average reduction in weight from baseline, and the percentage of people in each treatment arm achieving weight loss of at least 5% from baseline.
For both endpoints, the outcomes with tirzepatide significantly surpassed placebo effects. Average weight loss ranged from 15%-21% from baseline, depending on dose, compared with 3% on placebo. The rate of participants with at least a 5% weight loss ranged from 85% to 91%, compared with 35% with placebo, as reported in July 2022 in the New England Journal of Medicine.
Cutting fat mass, boosting lean mass
New results from the trial reported by Dr. Jastreboff included a cut in fat mass from 46.2% of total body mass at baseline to 38.5% after 72 weeks, compared with a change from 46.8% at baseline to 44.7% after 72 weeks in the placebo group. Concurrently, lean mass increased with tirzepatide treatment from 51.0% at baseline to 58.1% after 72 weeks.
Participants who received tirzepatide, compared with those who received placebo, had “proportionately greater decrease in fat mass and proportionately greater increase in lean mass” compared with those who received placebo, said Dr. Jastreboff, an endocrinologist and obesity medicine specialist with Yale Medicine in New Haven, Conn. “I was impressed by the amount of visceral fat lost.”
These effects translated into a significant reduction in fat mass-to-lean mass ratio among the people treated with tirzepatide, with the greatest reduction in those who lost at least 15% of their starting weight. In that subgroup the fat-to-lean mass ratio dropped from 0.94 at baseline to 0.64 after 72 weeks of treatment, she said.
Focus on diet quality
People treated with tirzepatide “eat so little food that we need to improve the quality of what they eat to protect their muscle,” commented Carel le Roux, MBChB, PhD, a professor in the Diabetes Complications Research Centre of University College Dublin. “You no longer need a dietitian to help people lose weight, because the drug does that. You need dietitians to look after the nutritional health of patients while they lose weight,” Dr. le Roux said in a separate session at the meeting.
Additional tests showed that blood glucose and insulin levels were all significantly lower among trial participants on all three doses of tirzepatide compared with those on placebo, and the tirzepatide-treated subjects also had significant, roughly twofold elevations in their insulin sensitivity measured by the Matsuda Index.
The impact of tirzepatide on glucose and insulin levels and on insulin sensitivity was similar regardless of whether study participants had normoglycemia or prediabetes at entry. By design, no study participants had diabetes.
The trial assessed patient-reported quality-of-life outcomes using the 36-Item Short Form Survey (SF-36). Participants had significant increases in all eight domains within the SF-36 at all three tirzepatide doses, compared with placebo, at 72 weeks, Dr. Jastreboff reported. Improvements in the physical function domain increased most notably among study participants on tirzepatide who had functional limitations at baseline. Heart rate rose among participants who received either of the two highest tirzepatide doses by 2.3-2.5 beats/min, comparable with the effect of other injected incretin-based treatments.
Lipids improve in those with type 2 diabetes
Tirzepatide treatment also results in a “secondary effect” of improving levels of several lipids in people with type 2 diabetes, according to a meta-analysis of findings from six randomized trials. The meta-analysis collectively involved 4,502 participants treated for numerous weeks with one of three doses of tirzepatide and 2,144 people in comparator groups, reported Dr. Karagiannis, a diabetes researcher at Aristotle University of Thessaloniki (Greece).
Among the significant lipid changes linked with tirzepatide treatment, compared with placebo, were an average 13 mg/dL decrease in LDL cholesterol, an average 6 mg/dL decrease in VLDL cholesterol, and an average 50 mg/dL decrease in triglycerides. In comparison to a GLP-1 receptor agonist, an average 25 mg/dL decrease in triglycerides and an average 4 mg/dL reduction in VLDL cholesterol were seen. And trials comparing tirzepatide with basal insulin saw average reductions of 7% in LDL cholesterol, 15% in VLDL cholesterol, 15% in triglycerides, and an 8% increase in HDL cholesterol.
Dr. Karagiannis highlighted that the clinical impact of these effects is unclear, although he noted that the average reduction in LDL cholesterol relative to placebo is of a magnitude that could have a modest effect on long-term outcomes.
These lipid effects of tirzepatide “should be considered alongside” tirzepatide’s “key metabolic effects” on weight and hemoglobin A1c as well as the drug’s safety, concluded Dr. Karagiannis.
The tirzepatide trials were all funded by Eli Lilly, which markets tirzepatide (Mounjaro). Dr. Jastreboff has been an adviser and consultant to Eli Lilly, as well as to Intellihealth, Novo Nordisk, Pfizer, Rhythm Scholars, Roche, and Weight Watchers, and she has received research funding from Eli Lilly and Novo Nordisk. Dr. Karagiannis had no disclosures. Dr. le Roux has had financial relationships with Eli Lilly, as well as with Boehringer Ingelheim, Consilient Health, Covidion, Fractyl, GL Dynamics, Herbalife, Johnson & Johnson, Keyron, and Novo Nordisk.
STOCKHOLM – New insights into the benefits of treatment with the “twincretin” tirzepatide for people with overweight or obesity – with or without diabetes – come from new findings reported at the annual meeting of the European Association for the Study of Diabetes.
Additional results from the SURMOUNT-1 trial, which matched tirzepatide against placebo in people with overweight or obesity, provide further details on the favorable changes produced by 72 weeks of tirzepatide treatment on outcomes that included fat and lean mass, insulin sensitivity, and patient-reported outcomes related to functional health and well being, reported Ania M. Jastreboff, MD, PhD.
And results from a meta-analysis of six trials that compared tirzepatide (Mounjaro) against several different comparators in patients with type 2 diabetes further confirm the drug’s ability to reliably produce positive changes in blood lipids, especially by significantly lowering levels of triglycerides, LDL cholesterol, and very LDL (VLDL) cholesterol, said Thomas Karagiannis, MD, PhD, in a separate report at the meeting.
Tirzepatide works as an agonist on receptors for both the glucagonlike peptide–1 (GLP-1), and for the glucose-dependent insulinotropic polypeptide, and received Food and Drug Administration approval for treating people with type 2 diabetes in May 2022. On the basis of results from SURMOUNT-1, the FDA on Oct. 6 granted tirzepatide fast-track designation for a proposed labeling of the agent for treating people with overweight or obesity. This FDA decision will likely remain pending at least until results from a second trial in people with overweight or obesity but without diabetes, SURMOUNT-2, become available in 2023.
SURMOUNT-1 randomized 2,539 people with obesity or overweight and at least one weight-related complication to a weekly injection of tirzepatide or placebo for 72 weeks. The study’s primary efficacy endpoints were the average reduction in weight from baseline, and the percentage of people in each treatment arm achieving weight loss of at least 5% from baseline.
For both endpoints, the outcomes with tirzepatide significantly surpassed placebo effects. Average weight loss ranged from 15%-21% from baseline, depending on dose, compared with 3% on placebo. The rate of participants with at least a 5% weight loss ranged from 85% to 91%, compared with 35% with placebo, as reported in July 2022 in the New England Journal of Medicine.
Cutting fat mass, boosting lean mass
New results from the trial reported by Dr. Jastreboff included a cut in fat mass from 46.2% of total body mass at baseline to 38.5% after 72 weeks, compared with a change from 46.8% at baseline to 44.7% after 72 weeks in the placebo group. Concurrently, lean mass increased with tirzepatide treatment from 51.0% at baseline to 58.1% after 72 weeks.
Participants who received tirzepatide, compared with those who received placebo, had “proportionately greater decrease in fat mass and proportionately greater increase in lean mass” compared with those who received placebo, said Dr. Jastreboff, an endocrinologist and obesity medicine specialist with Yale Medicine in New Haven, Conn. “I was impressed by the amount of visceral fat lost.”
These effects translated into a significant reduction in fat mass-to-lean mass ratio among the people treated with tirzepatide, with the greatest reduction in those who lost at least 15% of their starting weight. In that subgroup the fat-to-lean mass ratio dropped from 0.94 at baseline to 0.64 after 72 weeks of treatment, she said.
Focus on diet quality
People treated with tirzepatide “eat so little food that we need to improve the quality of what they eat to protect their muscle,” commented Carel le Roux, MBChB, PhD, a professor in the Diabetes Complications Research Centre of University College Dublin. “You no longer need a dietitian to help people lose weight, because the drug does that. You need dietitians to look after the nutritional health of patients while they lose weight,” Dr. le Roux said in a separate session at the meeting.
Additional tests showed that blood glucose and insulin levels were all significantly lower among trial participants on all three doses of tirzepatide compared with those on placebo, and the tirzepatide-treated subjects also had significant, roughly twofold elevations in their insulin sensitivity measured by the Matsuda Index.
The impact of tirzepatide on glucose and insulin levels and on insulin sensitivity was similar regardless of whether study participants had normoglycemia or prediabetes at entry. By design, no study participants had diabetes.
The trial assessed patient-reported quality-of-life outcomes using the 36-Item Short Form Survey (SF-36). Participants had significant increases in all eight domains within the SF-36 at all three tirzepatide doses, compared with placebo, at 72 weeks, Dr. Jastreboff reported. Improvements in the physical function domain increased most notably among study participants on tirzepatide who had functional limitations at baseline. Heart rate rose among participants who received either of the two highest tirzepatide doses by 2.3-2.5 beats/min, comparable with the effect of other injected incretin-based treatments.
Lipids improve in those with type 2 diabetes
Tirzepatide treatment also results in a “secondary effect” of improving levels of several lipids in people with type 2 diabetes, according to a meta-analysis of findings from six randomized trials. The meta-analysis collectively involved 4,502 participants treated for numerous weeks with one of three doses of tirzepatide and 2,144 people in comparator groups, reported Dr. Karagiannis, a diabetes researcher at Aristotle University of Thessaloniki (Greece).
Among the significant lipid changes linked with tirzepatide treatment, compared with placebo, were an average 13 mg/dL decrease in LDL cholesterol, an average 6 mg/dL decrease in VLDL cholesterol, and an average 50 mg/dL decrease in triglycerides. In comparison to a GLP-1 receptor agonist, an average 25 mg/dL decrease in triglycerides and an average 4 mg/dL reduction in VLDL cholesterol were seen. And trials comparing tirzepatide with basal insulin saw average reductions of 7% in LDL cholesterol, 15% in VLDL cholesterol, 15% in triglycerides, and an 8% increase in HDL cholesterol.
Dr. Karagiannis highlighted that the clinical impact of these effects is unclear, although he noted that the average reduction in LDL cholesterol relative to placebo is of a magnitude that could have a modest effect on long-term outcomes.
These lipid effects of tirzepatide “should be considered alongside” tirzepatide’s “key metabolic effects” on weight and hemoglobin A1c as well as the drug’s safety, concluded Dr. Karagiannis.
The tirzepatide trials were all funded by Eli Lilly, which markets tirzepatide (Mounjaro). Dr. Jastreboff has been an adviser and consultant to Eli Lilly, as well as to Intellihealth, Novo Nordisk, Pfizer, Rhythm Scholars, Roche, and Weight Watchers, and she has received research funding from Eli Lilly and Novo Nordisk. Dr. Karagiannis had no disclosures. Dr. le Roux has had financial relationships with Eli Lilly, as well as with Boehringer Ingelheim, Consilient Health, Covidion, Fractyl, GL Dynamics, Herbalife, Johnson & Johnson, Keyron, and Novo Nordisk.
AT EASD 2022
How to improve diagnosis of HFpEF, common in diabetes
STOCKHOLM – Recent study results confirm that two agents from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class can significantly cut the incidence of adverse cardiovascular events in patients with heart failure with reduced ejection fraction (HFpEF), a disease especially common in people with type 2 diabetes, obesity, or both.
And findings from secondary analyses of the studies – including one reported at the annual meeting of the European Association for the Study of Diabetes – show that these SGLT2 inhibitors work as well for cutting incident adverse events (cardiovascular death or worsening heart failure) in patients with HFpEF and diabetes as they do for people with normal blood glucose levels.
But delivering treatment with these proven agents, dapagliflozin (Farxiga) and empagliflozin (Jardiance), first requires diagnosis of HFpEF, a task that clinicians have historically fallen short in accomplishing.
When in 2021, results from the EMPEROR-Preserved trial with empagliflozin and when in September 2022 results from the DELIVER trial with dapagliflozin established the efficacy of these two SGLT2 inhibitors as the first treatments proven to benefit patients with HFpEF, they also raised the stakes for clinicians to be much more diligent and systematic in evaluating people at high risk for developing HFpEF because of having type 2 diabetes or obesity, two of the most potent risk factors for this form of heart failure.
‘Vigilance ... needs to increase’
“Vigilance for HFpEF needs to increase because we can now help these patients,” declared Lars H. Lund, MD, PhD, speaking at the meeting. “Type 2 diabetes dramatically increases the incidence of HFpEF,” and the mechanisms by which it does this are “especially amenable to treatment with SGLT2 inhibitors,” said Dr. Lund, a cardiologist and heart failure specialist at the Karolinska Institute, Stockholm.
HFpEF has a history of going undetected in people with type 2 diabetes, an ironic situation given its high incidence as well as the elevated rate of adverse cardiovascular events when heart failure occurs in patients with type 2 diabetes compared with patients who do not have diabetes.
The key, say experts, is for clinicians to maintain a high index of suspicion for signs and symptoms of heart failure in people with type 2 diabetes and to regularly assess them, starting with just a few simple questions that probe for the presence of dyspnea, exertional fatigue, or both, an approach not widely employed up to now.
Clinicians who care for people with type 2 diabetes must become “alert to thinking about heart failure and alert to asking questions about signs and symptoms” that flag the presence of HFpEF, advised Naveed Sattar, MBChB, PhD, a professor of metabolic medicine at the University of Glasgow.
Soon, medical groups will issue guidelines for appropriate assessment for the presence of HFpEF in people with type 2 diabetes, Dr. Sattar predicted in an interview.
A need to probe
“You can’t simply ask patients with type 2 diabetes whether they have shortness of breath or exertional fatigue and stop there,” because often their first response will be no.
“Commonly, patients will initially say they have no dyspnea, but when you probe further, you find symptoms,” noted Mikhail N. Kosiborod, MD, codirector of Saint Luke’s Cardiometabolic Center of Excellence in Kansas City, Mo.
These people are often sedentary, so they frequently don’t experience shortness of breath at baseline, Dr. Kosiborod said in an interview. In some cases, they may limit their activity because of their exertional intolerance.
Once a person’s suggestive symptoms become known, the next step is to measure the serum level of N-terminal pro-B-type natriuretic peptide (NT-proBNP), a biomarker considered to be a generally reliable signal of existing heart failure when elevated.
Any value above 125 pg/mL is suggestive of prevalent heart failure and should lead to the next diagnostic step of echocardiography, Dr. Sattar said.
Elevated NT-proBNP has such good positive predictive value for identifying heart failure that it is tempting to use it broadly in people with type 2 diabetes. A 2022 consensus report from the American Diabetes Association says that “measurement of a natriuretic peptide [such as NT-proBNP] or high-sensitivity cardiac troponin is recommended on at least a yearly basis to identify the earliest HF [heart failure] stages and implement strategies to prevent transition to symptomatic HF.”
Test costs require targeting
But because of the relatively high current price for an NT-proBNP test, the cost-benefit ratio for widespread annual testing of all people with type 2 diabetes would be poor, some experts caution.
“Screening everyone may not be the right answer. Hundreds of millions of people worldwide” have type 2 diabetes. “You first need to target evaluation to people with symptoms,” advised Dr. Kosiborod.
He also warned that a low NT-proBNP level does not always rule out HFpEF, especially among people with type 2 diabetes who also have overweight or obesity, because NT-proBNP levels can be “artificially low” in people with obesity.
Other potential aids to diagnosis are assessment scores that researchers have developed, such as the H2FPEF score, which relies on variables that include age, obesity, and the presence of atrial fibrillation and hypertension.
However, this score also requires an echocardiography examination, another test that would have a questionable cost-benefit ratio if performed widely for patients with type 2 diabetes without targeting, Dr. Kosiborod said.
SGLT2 inhibitors benefit HFpEF regardless of glucose levels
A prespecified analysis of the DELIVER results that divided the study cohort on the basis of their glycemic status proved the efficacy of the SGLT2 inhibitor dapagliflozin for patients with HFpEF regardless of whether or not they had type 2 diabetes, prediabetes, or were normoglycemic at entry into the study, Silvio E. Inzucchi, MD, reported at the EASD meeting.
Treatment with dapagliflozin cut the incidence of the trial’s primary outcome of cardiovascular death or worsening heart failure by a significant 18% relative to placebo among all enrolled patients.
The new analysis reported by Dr. Inzucchi showed that treatment was associated with a 23% relative risk reduction among those with normoglycemia, a 13% reduction among those with prediabetes, and a 19% reduction among those with type 2 diabetes, with no signal of a significant difference among the three subgroups.
“There was no statistical interaction between categorical glycemic subgrouping and dapagliflozin’s treatment effect,” concluded Dr. Inzucchi, director of the Yale Medicine Diabetes Center, New Haven, Conn.
He also reported that, among the 6,259 people in the trial with HFpEF, 50% had diabetes, 31% had prediabetes, and a scant 19% had normoglycemia. The finding highlights once again the high prevalence of dysglycemia among people with HFpEF.
Previously, a prespecified secondary analysis of data from the EMPEROR-Preserved trial yielded similar findings for empagliflozin that showed the agent’s efficacy for people with HFpEF across the range of glucose levels.
The DELIVER trial was funded by AstraZeneca, the company that markets dapagliflozin (Farxiga). The EMPEROR-Preserved trial was sponsored by Boehringer Ingelheim and Eli Lilly, the companies that jointly market empagliflozin (Jardiance). Dr. Lund has been a consultant to AstraZeneca and Boehringer Ingelheim and to numerous other companies, and he is a stockholder in AnaCardio. Dr. Sattar has been a consultant to and has received research support from AstraZeneca and Boehringer Ingelheim, and he has been a consultant with numerous companies. Dr. Kosiborod has been a consultant to and has received research funding from AstraZeneca and Boehringer Ingelheim and has been a consultant to Eli Lilly and numerous other companies. Dr. Inzucchi has been a consultant to, given talks on behalf of, or served on trial committees for Abbott, AstraZeneca, Boehringer Ingelheim, Esperion, Lexicon, Merck, Novo Nordisk, Pfizer, and vTv Therapetics.
A version of this article first appeared on Medscape.com.
STOCKHOLM – Recent study results confirm that two agents from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class can significantly cut the incidence of adverse cardiovascular events in patients with heart failure with reduced ejection fraction (HFpEF), a disease especially common in people with type 2 diabetes, obesity, or both.
And findings from secondary analyses of the studies – including one reported at the annual meeting of the European Association for the Study of Diabetes – show that these SGLT2 inhibitors work as well for cutting incident adverse events (cardiovascular death or worsening heart failure) in patients with HFpEF and diabetes as they do for people with normal blood glucose levels.
But delivering treatment with these proven agents, dapagliflozin (Farxiga) and empagliflozin (Jardiance), first requires diagnosis of HFpEF, a task that clinicians have historically fallen short in accomplishing.
When in 2021, results from the EMPEROR-Preserved trial with empagliflozin and when in September 2022 results from the DELIVER trial with dapagliflozin established the efficacy of these two SGLT2 inhibitors as the first treatments proven to benefit patients with HFpEF, they also raised the stakes for clinicians to be much more diligent and systematic in evaluating people at high risk for developing HFpEF because of having type 2 diabetes or obesity, two of the most potent risk factors for this form of heart failure.
‘Vigilance ... needs to increase’
“Vigilance for HFpEF needs to increase because we can now help these patients,” declared Lars H. Lund, MD, PhD, speaking at the meeting. “Type 2 diabetes dramatically increases the incidence of HFpEF,” and the mechanisms by which it does this are “especially amenable to treatment with SGLT2 inhibitors,” said Dr. Lund, a cardiologist and heart failure specialist at the Karolinska Institute, Stockholm.
HFpEF has a history of going undetected in people with type 2 diabetes, an ironic situation given its high incidence as well as the elevated rate of adverse cardiovascular events when heart failure occurs in patients with type 2 diabetes compared with patients who do not have diabetes.
The key, say experts, is for clinicians to maintain a high index of suspicion for signs and symptoms of heart failure in people with type 2 diabetes and to regularly assess them, starting with just a few simple questions that probe for the presence of dyspnea, exertional fatigue, or both, an approach not widely employed up to now.
Clinicians who care for people with type 2 diabetes must become “alert to thinking about heart failure and alert to asking questions about signs and symptoms” that flag the presence of HFpEF, advised Naveed Sattar, MBChB, PhD, a professor of metabolic medicine at the University of Glasgow.
Soon, medical groups will issue guidelines for appropriate assessment for the presence of HFpEF in people with type 2 diabetes, Dr. Sattar predicted in an interview.
A need to probe
“You can’t simply ask patients with type 2 diabetes whether they have shortness of breath or exertional fatigue and stop there,” because often their first response will be no.
“Commonly, patients will initially say they have no dyspnea, but when you probe further, you find symptoms,” noted Mikhail N. Kosiborod, MD, codirector of Saint Luke’s Cardiometabolic Center of Excellence in Kansas City, Mo.
These people are often sedentary, so they frequently don’t experience shortness of breath at baseline, Dr. Kosiborod said in an interview. In some cases, they may limit their activity because of their exertional intolerance.
Once a person’s suggestive symptoms become known, the next step is to measure the serum level of N-terminal pro-B-type natriuretic peptide (NT-proBNP), a biomarker considered to be a generally reliable signal of existing heart failure when elevated.
Any value above 125 pg/mL is suggestive of prevalent heart failure and should lead to the next diagnostic step of echocardiography, Dr. Sattar said.
Elevated NT-proBNP has such good positive predictive value for identifying heart failure that it is tempting to use it broadly in people with type 2 diabetes. A 2022 consensus report from the American Diabetes Association says that “measurement of a natriuretic peptide [such as NT-proBNP] or high-sensitivity cardiac troponin is recommended on at least a yearly basis to identify the earliest HF [heart failure] stages and implement strategies to prevent transition to symptomatic HF.”
Test costs require targeting
But because of the relatively high current price for an NT-proBNP test, the cost-benefit ratio for widespread annual testing of all people with type 2 diabetes would be poor, some experts caution.
“Screening everyone may not be the right answer. Hundreds of millions of people worldwide” have type 2 diabetes. “You first need to target evaluation to people with symptoms,” advised Dr. Kosiborod.
He also warned that a low NT-proBNP level does not always rule out HFpEF, especially among people with type 2 diabetes who also have overweight or obesity, because NT-proBNP levels can be “artificially low” in people with obesity.
Other potential aids to diagnosis are assessment scores that researchers have developed, such as the H2FPEF score, which relies on variables that include age, obesity, and the presence of atrial fibrillation and hypertension.
However, this score also requires an echocardiography examination, another test that would have a questionable cost-benefit ratio if performed widely for patients with type 2 diabetes without targeting, Dr. Kosiborod said.
SGLT2 inhibitors benefit HFpEF regardless of glucose levels
A prespecified analysis of the DELIVER results that divided the study cohort on the basis of their glycemic status proved the efficacy of the SGLT2 inhibitor dapagliflozin for patients with HFpEF regardless of whether or not they had type 2 diabetes, prediabetes, or were normoglycemic at entry into the study, Silvio E. Inzucchi, MD, reported at the EASD meeting.
Treatment with dapagliflozin cut the incidence of the trial’s primary outcome of cardiovascular death or worsening heart failure by a significant 18% relative to placebo among all enrolled patients.
The new analysis reported by Dr. Inzucchi showed that treatment was associated with a 23% relative risk reduction among those with normoglycemia, a 13% reduction among those with prediabetes, and a 19% reduction among those with type 2 diabetes, with no signal of a significant difference among the three subgroups.
“There was no statistical interaction between categorical glycemic subgrouping and dapagliflozin’s treatment effect,” concluded Dr. Inzucchi, director of the Yale Medicine Diabetes Center, New Haven, Conn.
He also reported that, among the 6,259 people in the trial with HFpEF, 50% had diabetes, 31% had prediabetes, and a scant 19% had normoglycemia. The finding highlights once again the high prevalence of dysglycemia among people with HFpEF.
Previously, a prespecified secondary analysis of data from the EMPEROR-Preserved trial yielded similar findings for empagliflozin that showed the agent’s efficacy for people with HFpEF across the range of glucose levels.
The DELIVER trial was funded by AstraZeneca, the company that markets dapagliflozin (Farxiga). The EMPEROR-Preserved trial was sponsored by Boehringer Ingelheim and Eli Lilly, the companies that jointly market empagliflozin (Jardiance). Dr. Lund has been a consultant to AstraZeneca and Boehringer Ingelheim and to numerous other companies, and he is a stockholder in AnaCardio. Dr. Sattar has been a consultant to and has received research support from AstraZeneca and Boehringer Ingelheim, and he has been a consultant with numerous companies. Dr. Kosiborod has been a consultant to and has received research funding from AstraZeneca and Boehringer Ingelheim and has been a consultant to Eli Lilly and numerous other companies. Dr. Inzucchi has been a consultant to, given talks on behalf of, or served on trial committees for Abbott, AstraZeneca, Boehringer Ingelheim, Esperion, Lexicon, Merck, Novo Nordisk, Pfizer, and vTv Therapetics.
A version of this article first appeared on Medscape.com.
STOCKHOLM – Recent study results confirm that two agents from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class can significantly cut the incidence of adverse cardiovascular events in patients with heart failure with reduced ejection fraction (HFpEF), a disease especially common in people with type 2 diabetes, obesity, or both.
And findings from secondary analyses of the studies – including one reported at the annual meeting of the European Association for the Study of Diabetes – show that these SGLT2 inhibitors work as well for cutting incident adverse events (cardiovascular death or worsening heart failure) in patients with HFpEF and diabetes as they do for people with normal blood glucose levels.
But delivering treatment with these proven agents, dapagliflozin (Farxiga) and empagliflozin (Jardiance), first requires diagnosis of HFpEF, a task that clinicians have historically fallen short in accomplishing.
When in 2021, results from the EMPEROR-Preserved trial with empagliflozin and when in September 2022 results from the DELIVER trial with dapagliflozin established the efficacy of these two SGLT2 inhibitors as the first treatments proven to benefit patients with HFpEF, they also raised the stakes for clinicians to be much more diligent and systematic in evaluating people at high risk for developing HFpEF because of having type 2 diabetes or obesity, two of the most potent risk factors for this form of heart failure.
‘Vigilance ... needs to increase’
“Vigilance for HFpEF needs to increase because we can now help these patients,” declared Lars H. Lund, MD, PhD, speaking at the meeting. “Type 2 diabetes dramatically increases the incidence of HFpEF,” and the mechanisms by which it does this are “especially amenable to treatment with SGLT2 inhibitors,” said Dr. Lund, a cardiologist and heart failure specialist at the Karolinska Institute, Stockholm.
HFpEF has a history of going undetected in people with type 2 diabetes, an ironic situation given its high incidence as well as the elevated rate of adverse cardiovascular events when heart failure occurs in patients with type 2 diabetes compared with patients who do not have diabetes.
The key, say experts, is for clinicians to maintain a high index of suspicion for signs and symptoms of heart failure in people with type 2 diabetes and to regularly assess them, starting with just a few simple questions that probe for the presence of dyspnea, exertional fatigue, or both, an approach not widely employed up to now.
Clinicians who care for people with type 2 diabetes must become “alert to thinking about heart failure and alert to asking questions about signs and symptoms” that flag the presence of HFpEF, advised Naveed Sattar, MBChB, PhD, a professor of metabolic medicine at the University of Glasgow.
Soon, medical groups will issue guidelines for appropriate assessment for the presence of HFpEF in people with type 2 diabetes, Dr. Sattar predicted in an interview.
A need to probe
“You can’t simply ask patients with type 2 diabetes whether they have shortness of breath or exertional fatigue and stop there,” because often their first response will be no.
“Commonly, patients will initially say they have no dyspnea, but when you probe further, you find symptoms,” noted Mikhail N. Kosiborod, MD, codirector of Saint Luke’s Cardiometabolic Center of Excellence in Kansas City, Mo.
These people are often sedentary, so they frequently don’t experience shortness of breath at baseline, Dr. Kosiborod said in an interview. In some cases, they may limit their activity because of their exertional intolerance.
Once a person’s suggestive symptoms become known, the next step is to measure the serum level of N-terminal pro-B-type natriuretic peptide (NT-proBNP), a biomarker considered to be a generally reliable signal of existing heart failure when elevated.
Any value above 125 pg/mL is suggestive of prevalent heart failure and should lead to the next diagnostic step of echocardiography, Dr. Sattar said.
Elevated NT-proBNP has such good positive predictive value for identifying heart failure that it is tempting to use it broadly in people with type 2 diabetes. A 2022 consensus report from the American Diabetes Association says that “measurement of a natriuretic peptide [such as NT-proBNP] or high-sensitivity cardiac troponin is recommended on at least a yearly basis to identify the earliest HF [heart failure] stages and implement strategies to prevent transition to symptomatic HF.”
Test costs require targeting
But because of the relatively high current price for an NT-proBNP test, the cost-benefit ratio for widespread annual testing of all people with type 2 diabetes would be poor, some experts caution.
“Screening everyone may not be the right answer. Hundreds of millions of people worldwide” have type 2 diabetes. “You first need to target evaluation to people with symptoms,” advised Dr. Kosiborod.
He also warned that a low NT-proBNP level does not always rule out HFpEF, especially among people with type 2 diabetes who also have overweight or obesity, because NT-proBNP levels can be “artificially low” in people with obesity.
Other potential aids to diagnosis are assessment scores that researchers have developed, such as the H2FPEF score, which relies on variables that include age, obesity, and the presence of atrial fibrillation and hypertension.
However, this score also requires an echocardiography examination, another test that would have a questionable cost-benefit ratio if performed widely for patients with type 2 diabetes without targeting, Dr. Kosiborod said.
SGLT2 inhibitors benefit HFpEF regardless of glucose levels
A prespecified analysis of the DELIVER results that divided the study cohort on the basis of their glycemic status proved the efficacy of the SGLT2 inhibitor dapagliflozin for patients with HFpEF regardless of whether or not they had type 2 diabetes, prediabetes, or were normoglycemic at entry into the study, Silvio E. Inzucchi, MD, reported at the EASD meeting.
Treatment with dapagliflozin cut the incidence of the trial’s primary outcome of cardiovascular death or worsening heart failure by a significant 18% relative to placebo among all enrolled patients.
The new analysis reported by Dr. Inzucchi showed that treatment was associated with a 23% relative risk reduction among those with normoglycemia, a 13% reduction among those with prediabetes, and a 19% reduction among those with type 2 diabetes, with no signal of a significant difference among the three subgroups.
“There was no statistical interaction between categorical glycemic subgrouping and dapagliflozin’s treatment effect,” concluded Dr. Inzucchi, director of the Yale Medicine Diabetes Center, New Haven, Conn.
He also reported that, among the 6,259 people in the trial with HFpEF, 50% had diabetes, 31% had prediabetes, and a scant 19% had normoglycemia. The finding highlights once again the high prevalence of dysglycemia among people with HFpEF.
Previously, a prespecified secondary analysis of data from the EMPEROR-Preserved trial yielded similar findings for empagliflozin that showed the agent’s efficacy for people with HFpEF across the range of glucose levels.
The DELIVER trial was funded by AstraZeneca, the company that markets dapagliflozin (Farxiga). The EMPEROR-Preserved trial was sponsored by Boehringer Ingelheim and Eli Lilly, the companies that jointly market empagliflozin (Jardiance). Dr. Lund has been a consultant to AstraZeneca and Boehringer Ingelheim and to numerous other companies, and he is a stockholder in AnaCardio. Dr. Sattar has been a consultant to and has received research support from AstraZeneca and Boehringer Ingelheim, and he has been a consultant with numerous companies. Dr. Kosiborod has been a consultant to and has received research funding from AstraZeneca and Boehringer Ingelheim and has been a consultant to Eli Lilly and numerous other companies. Dr. Inzucchi has been a consultant to, given talks on behalf of, or served on trial committees for Abbott, AstraZeneca, Boehringer Ingelheim, Esperion, Lexicon, Merck, Novo Nordisk, Pfizer, and vTv Therapetics.
A version of this article first appeared on Medscape.com.
AT EASD 2022