Cardiology News

CHICAGO – Early ablation of atrial fibrillation (AFib) reduces the risk of progression, compared with antiarrhythmic therapies, according to results of a multicenter, randomized trial called PROGRESSIVE-AF.

Over 36 months of follow-up, the trial linked early ablation with a reduced risk of persistent AFib (1.9% vs. 7.4%), and in addition, those in the ablation group were less likely to have recurrent atrial tachyarrhythmias of any kind (56.5% vs. 77.2%), reported Jason G. Andrade, MD, at the American Heart Association scientific sessions.

Ted Bosworth/MDedge

Serving as a long-term extension of the EARLY-AF trial published almost 2 years ago, this trial expands evidence that progressive AFib can be attenuated, a concept that has been debated.

“Can early AFib ablation stop progression?” asked Carina Blomström-Lindqvist, MD, PhD. The invited discussant for the PROGRESSION-AF trial, Dr. Blomström-Lundqvist concluded, “here is another set of data that suggests it can.”

By another set of data, Dr. Blomström-Lindqvist was referring to a previously published multinational study called ATTEST In this study, which involved 29 sites worldwide and compared radiofrequency ablation to antiarrhythmic drug therapy, early ablation also produced a lower risk of persistent AFib at the end of 3 years (2.4% vs. 17.5%; P = .0009).

In the previously published open-label EARLY-AF trial, 303 patients with paroxysmal, untreated AFib were randomized to cryoballoon ablation or antiarrhythmic drugs. The primary endpoint was the first documented recurrence of an atrial tachyarrhythmia between 91 and 365 days. The lower rate following ablation (42.9% vs. 67.8%) represented a more than 50% reduction in risk (hazard ratio, 0.48; P < .001) relative to antiarrhythmic therapy.

In PROGRESSIVE-AF, the same 303 patients were monitored continuously for an additional 24 months with an implanted cardiac monitor programmed with an AFib-detection algorithm. The data from the monitor were obtained daily. Over the final 2 years of the study, office visits were conducted every 6 months.
 

Tachyarrhythmias represent primary endpoint

In addition to persistent AFib, defined as lasting ≥ 7 days or lasting 48 hours to 7 days but requiring cardioversion for termination, patients in PROGRESSIVE-AF were also monitored for recurrent atrial tachyarrhythmias, AFib burden, quality of life (QOL), and health care utilization, and safety.

The average age was roughly 58 years. Although more than one-third had hypertension, most had no other comorbidities. The authors emphasized that the study population overall was relatively young and healthy.

Those randomized to antiarrhythmic therapy in EARLY-AF/PROGRESSIVE-AF received commonly prescribed therapies titrated to maximally tolerated doses using standardized protocols. At the start of EARLY-AF, flecainide, taken by 65% of patients, was the most commonly used agent, followed by sotalol, propafenone, dronedarone, and amiodarone.

At the end of PROGRESSIVE-AF, the order of the most common therapies did not change relative to EARLY-AF, but only 49% of patients were taking flecainide and 31% were no longer taking any antiarrhythmic therapy.

At the end of 3 years of follow-up in EARLY-AF/PROGRESSIVE-AF, the difference in persistent AFib represented a 75% reduction in favor of early ablation (HR, 0.25; 95% confidence interval, 0.09-0.70).

In those treated with ablation relative to those treated with antiarrhythmic therapy, the lower rate of atrial tachyarrhythmia lasting more than 7 days (1.9% vs. 6.0%) represented a 70% risk reduction (HR, 0.30; 95% CI 0.10-0.93). The protection from cardioversion for atrial tachyarrhythmia lasting between 2 and 7 days in duration (0.6% vs. 4.7%) translated into an 86% relative reduction (HR, 0.14; 95% CI, 0.02-0.85).

The impact on QOL for those randomized to ablation, which was measured with both AFib-specific and generic measures, was meaningful to patients, according to Dr. Andrade, director of the Cardiac Electrophysiology Laboratory, Vancouver General Hospital.

For example, the mean difference in the AF Quality of Life Survey (AFEQT), was 8.0 at 1 year and 7.4 at 3 years in favor of ablation. A change of 5 points in this score is considered to be a clinically meaningful difference, according to Dr. Andrade.

Numerically, the relative risk of emergency room visits and cardioversion were lower in the ablation group, but the differences did not reach statistical significance. However, the lower hazard ratio for hospitalization was significant (HR, 0.31; 95% CI, 0.15-0.66), supporting a reduction in consumption of health care resources.
 

Ablation found safer than drugs

The rate of adverse events of any kind (11.0% vs. 23.5%) and serious adverse events (4.5% vs. 10.1%) were lower in the ablation group.

There were no differences in major adverse cardiovascular events observed in this period of follow-up, but Dr. Andrade pointed out that follow-up was not long enough to expect differences in these events.

Impressed by the magnitude of the reduction in persistent AFib in a population of relatively young and healthy patients considered to be at a low risk of AFib progression, Dr. Blomström-Lindqvist, a professor of cardiology at the Institution of Medical Science, Uppsala, Sweden, indicated that the data support early ablation as a means to reduce risk of this outcome.

However, she did caution that progressive AFib was observed in a relatively small proportion of patients managed with antiarrhythmic therapy at 3 years, an outcome relevant when discussing treatment options with patients.

The results were published in New England Journal of Medicine simultaneously with Dr. Andrade’s presentation.

Dr. Andrade reports financial relationships with Bayer, Bayliss, Biosense, Bristol-Myers Squibb, Medtronic and Servier. The trial, funded largely by the Canadian government and Canadian professional societies, received additional funding from Bayliss and Medtronic. Dr. Blomström-Lundqvist reports financial relationships with Bayer, Boston Scientific, Cathprint, Medtronic, and Sanofi.

CHICAGO – Early ablation of atrial fibrillation (AFib) reduces the risk of progression, compared with antiarrhythmic therapies, according to results of a multicenter, randomized trial called PROGRESSIVE-AF.

Over 36 months of follow-up, the trial linked early ablation with a reduced risk of persistent AFib (1.9% vs. 7.4%), and in addition, those in the ablation group were less likely to have recurrent atrial tachyarrhythmias of any kind (56.5% vs. 77.2%), reported Jason G. Andrade, MD, at the American Heart Association scientific sessions.

Ted Bosworth/MDedge

Serving as a long-term extension of the EARLY-AF trial published almost 2 years ago, this trial expands evidence that progressive AFib can be attenuated, a concept that has been debated.

“Can early AFib ablation stop progression?” asked Carina Blomström-Lindqvist, MD, PhD. The invited discussant for the PROGRESSION-AF trial, Dr. Blomström-Lundqvist concluded, “here is another set of data that suggests it can.”

By another set of data, Dr. Blomström-Lindqvist was referring to a previously published multinational study called ATTEST In this study, which involved 29 sites worldwide and compared radiofrequency ablation to antiarrhythmic drug therapy, early ablation also produced a lower risk of persistent AFib at the end of 3 years (2.4% vs. 17.5%; P = .0009).

In the previously published open-label EARLY-AF trial, 303 patients with paroxysmal, untreated AFib were randomized to cryoballoon ablation or antiarrhythmic drugs. The primary endpoint was the first documented recurrence of an atrial tachyarrhythmia between 91 and 365 days. The lower rate following ablation (42.9% vs. 67.8%) represented a more than 50% reduction in risk (hazard ratio, 0.48; P < .001) relative to antiarrhythmic therapy.

In PROGRESSIVE-AF, the same 303 patients were monitored continuously for an additional 24 months with an implanted cardiac monitor programmed with an AFib-detection algorithm. The data from the monitor were obtained daily. Over the final 2 years of the study, office visits were conducted every 6 months.
 

Tachyarrhythmias represent primary endpoint

In addition to persistent AFib, defined as lasting ≥ 7 days or lasting 48 hours to 7 days but requiring cardioversion for termination, patients in PROGRESSIVE-AF were also monitored for recurrent atrial tachyarrhythmias, AFib burden, quality of life (QOL), and health care utilization, and safety.

The average age was roughly 58 years. Although more than one-third had hypertension, most had no other comorbidities. The authors emphasized that the study population overall was relatively young and healthy.

Those randomized to antiarrhythmic therapy in EARLY-AF/PROGRESSIVE-AF received commonly prescribed therapies titrated to maximally tolerated doses using standardized protocols. At the start of EARLY-AF, flecainide, taken by 65% of patients, was the most commonly used agent, followed by sotalol, propafenone, dronedarone, and amiodarone.

At the end of PROGRESSIVE-AF, the order of the most common therapies did not change relative to EARLY-AF, but only 49% of patients were taking flecainide and 31% were no longer taking any antiarrhythmic therapy.

At the end of 3 years of follow-up in EARLY-AF/PROGRESSIVE-AF, the difference in persistent AFib represented a 75% reduction in favor of early ablation (HR, 0.25; 95% confidence interval, 0.09-0.70).

In those treated with ablation relative to those treated with antiarrhythmic therapy, the lower rate of atrial tachyarrhythmia lasting more than 7 days (1.9% vs. 6.0%) represented a 70% risk reduction (HR, 0.30; 95% CI 0.10-0.93). The protection from cardioversion for atrial tachyarrhythmia lasting between 2 and 7 days in duration (0.6% vs. 4.7%) translated into an 86% relative reduction (HR, 0.14; 95% CI, 0.02-0.85).

The impact on QOL for those randomized to ablation, which was measured with both AFib-specific and generic measures, was meaningful to patients, according to Dr. Andrade, director of the Cardiac Electrophysiology Laboratory, Vancouver General Hospital.

For example, the mean difference in the AF Quality of Life Survey (AFEQT), was 8.0 at 1 year and 7.4 at 3 years in favor of ablation. A change of 5 points in this score is considered to be a clinically meaningful difference, according to Dr. Andrade.

Numerically, the relative risk of emergency room visits and cardioversion were lower in the ablation group, but the differences did not reach statistical significance. However, the lower hazard ratio for hospitalization was significant (HR, 0.31; 95% CI, 0.15-0.66), supporting a reduction in consumption of health care resources.
 

Ablation found safer than drugs

The rate of adverse events of any kind (11.0% vs. 23.5%) and serious adverse events (4.5% vs. 10.1%) were lower in the ablation group.

There were no differences in major adverse cardiovascular events observed in this period of follow-up, but Dr. Andrade pointed out that follow-up was not long enough to expect differences in these events.

Impressed by the magnitude of the reduction in persistent AFib in a population of relatively young and healthy patients considered to be at a low risk of AFib progression, Dr. Blomström-Lindqvist, a professor of cardiology at the Institution of Medical Science, Uppsala, Sweden, indicated that the data support early ablation as a means to reduce risk of this outcome.

However, she did caution that progressive AFib was observed in a relatively small proportion of patients managed with antiarrhythmic therapy at 3 years, an outcome relevant when discussing treatment options with patients.

The results were published in New England Journal of Medicine simultaneously with Dr. Andrade’s presentation.

Dr. Andrade reports financial relationships with Bayer, Bayliss, Biosense, Bristol-Myers Squibb, Medtronic and Servier. The trial, funded largely by the Canadian government and Canadian professional societies, received additional funding from Bayliss and Medtronic. Dr. Blomström-Lundqvist reports financial relationships with Bayer, Boston Scientific, Cathprint, Medtronic, and Sanofi.

CHICAGO – Early ablation of atrial fibrillation (AFib) reduces the risk of progression, compared with antiarrhythmic therapies, according to results of a multicenter, randomized trial called PROGRESSIVE-AF.

Over 36 months of follow-up, the trial linked early ablation with a reduced risk of persistent AFib (1.9% vs. 7.4%), and in addition, those in the ablation group were less likely to have recurrent atrial tachyarrhythmias of any kind (56.5% vs. 77.2%), reported Jason G. Andrade, MD, at the American Heart Association scientific sessions.

Ted Bosworth/MDedge

Serving as a long-term extension of the EARLY-AF trial published almost 2 years ago, this trial expands evidence that progressive AFib can be attenuated, a concept that has been debated.

“Can early AFib ablation stop progression?” asked Carina Blomström-Lindqvist, MD, PhD. The invited discussant for the PROGRESSION-AF trial, Dr. Blomström-Lundqvist concluded, “here is another set of data that suggests it can.”

By another set of data, Dr. Blomström-Lindqvist was referring to a previously published multinational study called ATTEST In this study, which involved 29 sites worldwide and compared radiofrequency ablation to antiarrhythmic drug therapy, early ablation also produced a lower risk of persistent AFib at the end of 3 years (2.4% vs. 17.5%; P = .0009).

In the previously published open-label EARLY-AF trial, 303 patients with paroxysmal, untreated AFib were randomized to cryoballoon ablation or antiarrhythmic drugs. The primary endpoint was the first documented recurrence of an atrial tachyarrhythmia between 91 and 365 days. The lower rate following ablation (42.9% vs. 67.8%) represented a more than 50% reduction in risk (hazard ratio, 0.48; P < .001) relative to antiarrhythmic therapy.

In PROGRESSIVE-AF, the same 303 patients were monitored continuously for an additional 24 months with an implanted cardiac monitor programmed with an AFib-detection algorithm. The data from the monitor were obtained daily. Over the final 2 years of the study, office visits were conducted every 6 months.
 

Tachyarrhythmias represent primary endpoint

In addition to persistent AFib, defined as lasting ≥ 7 days or lasting 48 hours to 7 days but requiring cardioversion for termination, patients in PROGRESSIVE-AF were also monitored for recurrent atrial tachyarrhythmias, AFib burden, quality of life (QOL), and health care utilization, and safety.

The average age was roughly 58 years. Although more than one-third had hypertension, most had no other comorbidities. The authors emphasized that the study population overall was relatively young and healthy.

Those randomized to antiarrhythmic therapy in EARLY-AF/PROGRESSIVE-AF received commonly prescribed therapies titrated to maximally tolerated doses using standardized protocols. At the start of EARLY-AF, flecainide, taken by 65% of patients, was the most commonly used agent, followed by sotalol, propafenone, dronedarone, and amiodarone.

At the end of PROGRESSIVE-AF, the order of the most common therapies did not change relative to EARLY-AF, but only 49% of patients were taking flecainide and 31% were no longer taking any antiarrhythmic therapy.

At the end of 3 years of follow-up in EARLY-AF/PROGRESSIVE-AF, the difference in persistent AFib represented a 75% reduction in favor of early ablation (HR, 0.25; 95% confidence interval, 0.09-0.70).

In those treated with ablation relative to those treated with antiarrhythmic therapy, the lower rate of atrial tachyarrhythmia lasting more than 7 days (1.9% vs. 6.0%) represented a 70% risk reduction (HR, 0.30; 95% CI 0.10-0.93). The protection from cardioversion for atrial tachyarrhythmia lasting between 2 and 7 days in duration (0.6% vs. 4.7%) translated into an 86% relative reduction (HR, 0.14; 95% CI, 0.02-0.85).

The impact on QOL for those randomized to ablation, which was measured with both AFib-specific and generic measures, was meaningful to patients, according to Dr. Andrade, director of the Cardiac Electrophysiology Laboratory, Vancouver General Hospital.

For example, the mean difference in the AF Quality of Life Survey (AFEQT), was 8.0 at 1 year and 7.4 at 3 years in favor of ablation. A change of 5 points in this score is considered to be a clinically meaningful difference, according to Dr. Andrade.

Numerically, the relative risk of emergency room visits and cardioversion were lower in the ablation group, but the differences did not reach statistical significance. However, the lower hazard ratio for hospitalization was significant (HR, 0.31; 95% CI, 0.15-0.66), supporting a reduction in consumption of health care resources.
 

Ablation found safer than drugs

The rate of adverse events of any kind (11.0% vs. 23.5%) and serious adverse events (4.5% vs. 10.1%) were lower in the ablation group.

There were no differences in major adverse cardiovascular events observed in this period of follow-up, but Dr. Andrade pointed out that follow-up was not long enough to expect differences in these events.

Impressed by the magnitude of the reduction in persistent AFib in a population of relatively young and healthy patients considered to be at a low risk of AFib progression, Dr. Blomström-Lindqvist, a professor of cardiology at the Institution of Medical Science, Uppsala, Sweden, indicated that the data support early ablation as a means to reduce risk of this outcome.

However, she did caution that progressive AFib was observed in a relatively small proportion of patients managed with antiarrhythmic therapy at 3 years, an outcome relevant when discussing treatment options with patients.

The results were published in New England Journal of Medicine simultaneously with Dr. Andrade’s presentation.

Dr. Andrade reports financial relationships with Bayer, Bayliss, Biosense, Bristol-Myers Squibb, Medtronic and Servier. The trial, funded largely by the Canadian government and Canadian professional societies, received additional funding from Bayliss and Medtronic. Dr. Blomström-Lundqvist reports financial relationships with Bayer, Boston Scientific, Cathprint, Medtronic, and Sanofi.

SAN DIEGO – A novel glucagonlike peptide-1 (GLP-1)/glucagon dual-receptor agonist, BI 456906, being developed by Boehringer Ingelheim and Zealand Pharma, led to “impressive” weight loss in a phase 2 dosing study of patients with overweight/obesity and type 2 diabetes – but this is early research.

Julio Rosenstock, MD, presented the study results, including weight loss and adverse events, at the annual meeting of the Obesity Society.

At the highest tested dose (1.8 mg twice weekly subcutaneous injections), 57% of patients lost at least 5% of their initial body weight and 35% lost at least 10% of their initial body weight at 16 weeks.

In contrast, among the patients who received a 1-mg semaglutide dose as a comparator, 38% lost at least 5% of their initial body weight and 16% lost at least 10% of their initial body weight at study end.

Sara Freeman/MDedge News

This is “very promising data as an anti-obesity compound,” said Dr. Rosenstock, professor of medicine, University of Texas Southwestern Medical Center in Dallas.

The researchers enrolled 411 adults and randomized them into eight groups of roughly 50 patients each.

They compared six doses of BI 456906 (from 0.3 mg/week to 1.8 mg twice weekly) versus 1 mg/week of the GLP-1 agonist semaglutide (Wegovy, Novo Nordisk) versus placebo.

Patients had a mean initial weight of 97 kg (214 pounds).

After 4 months, on average, patients who received the highest tested dose of BI 456906 lost 9% of their initial weight or roughly 8.7 kg (19 pounds).

Patients who received semaglutide lost 5.4% of their initial weight or roughly 5.2 kg (11.5 pounds), and patients who received placebo lost only 1.2% of their initial weight

The main adverse events were gastrointestinal.
 

‘Exciting data,’ but still early days

“This is very exciting data. It comes from another experienced company with a track record of successful products with a new compound in a class where other related compounds have shown efficacy and safety,” Dan Bessesen, MD, president of The Obesity Society, who was not involved with this research, told this news organization in an email.

“The degree of weight loss is impressive for a 16-week study,” Dr. Bessesen, professor of medicine in the division of endocrinology, metabolism and diabetes at the University of Colorado at Denver, Aurora, added. “The longer-term weight loss will likely be more.”

The side-effect profile is not particularly concerning and is like other drugs in this general class, he said.

However, he also noted a few caveats. This was only a phase 2 study, “so we should not make firm conclusions about efficacy from a study like this, as the number of subjects studied at each dose is relatively small and the follow-up not long.”

In addition, “the dose of semaglutide is the old ‘diabetes’ dose (1 mg) not the weight-loss dose of 2.4 mg or the new diabetes dose of 2 mg. It is not a real comparison with the maximal approved dose of semaglutide. So, we cannot say that it will be better than semaglutide.”

The next hurdle is the “need to see phase 3 studies in a larger group of patients studied for a longer time. Then [the company] will need FDA approval, so it may be a bit of time” before this drug potentially enters the marketplace.

The “bottom line” is that this potential new antiobesity/diabetes drug is “very promising, but [it is] still a little early to say where it ultimately will go.”
 

A1c results presented at EASD

To be included in this study, patients had to be 18-75 years old, have type 2 diabetes, a body mass index of 25-50 kg/m², and hemoglobin A1c of 7%-10%, and be stable on metformin therapy.

The patients had a mean age of 57 years, and 57% were men. They had a mean A1c of 8.1%, a mean BMI of 34 kg/m², and a mean waist circumference of 110 cm (43 inches).

“We just recently reported at the EASD conference last month, the effect of BI 456906 on A1c lowering,” Dr. Rosenstock said.

“It looks like the [drop in] A1c plateaus at 1.9%, which is pretty good when you consider the baseline A1c is around 8%. You get down to around 6%, which is what we regard as a very robust reduction in people with type 2 diabetes on metformin.”

The current analysis showed that patients who received doses of 0.3, 0.9, 1.8, and 2.7 mg/week of the novel drug lost 1.9%, 4.4%, 6.6%, and 6.7% of their initial body weight, respectively, after 16 weeks.

The patients who received 1.2 mg and 1.8 mg twice weekly lost even more weight, 7.2% and 9% of their initial weight, respectively.

At the highest dose, on average, patients lost 13 cm (5 inches) around their waist.

Adverse events were reported by 78% of the patients, most commonly nausea (34% of patients), vomiting (18%), and diarrhea (16%).

Only 1.3% of patients had a drug-related serious adverse event. A total of 16% of patients discontinued the therapy.

Most of the “gastrointestinal adverse events leading the treatment discontinuation were possibly dose and titration related,” Dr. Rosenstock said, “and it’s highly conceivable that for future studies a slower dose escalation may mitigate the occurrence of the gastrointestinal adverse events.”

BI 456906 was coinvented with Zealand Pharma. Under the licensing agreement, Boehringer Ingelheim funds all research, development, and commercialization.

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

SAN DIEGO – A novel glucagonlike peptide-1 (GLP-1)/glucagon dual-receptor agonist, BI 456906, being developed by Boehringer Ingelheim and Zealand Pharma, led to “impressive” weight loss in a phase 2 dosing study of patients with overweight/obesity and type 2 diabetes – but this is early research.

Julio Rosenstock, MD, presented the study results, including weight loss and adverse events, at the annual meeting of the Obesity Society.

At the highest tested dose (1.8 mg twice weekly subcutaneous injections), 57% of patients lost at least 5% of their initial body weight and 35% lost at least 10% of their initial body weight at 16 weeks.

In contrast, among the patients who received a 1-mg semaglutide dose as a comparator, 38% lost at least 5% of their initial body weight and 16% lost at least 10% of their initial body weight at study end.

Sara Freeman/MDedge News

This is “very promising data as an anti-obesity compound,” said Dr. Rosenstock, professor of medicine, University of Texas Southwestern Medical Center in Dallas.

The researchers enrolled 411 adults and randomized them into eight groups of roughly 50 patients each.

They compared six doses of BI 456906 (from 0.3 mg/week to 1.8 mg twice weekly) versus 1 mg/week of the GLP-1 agonist semaglutide (Wegovy, Novo Nordisk) versus placebo.

Patients had a mean initial weight of 97 kg (214 pounds).

After 4 months, on average, patients who received the highest tested dose of BI 456906 lost 9% of their initial weight or roughly 8.7 kg (19 pounds).

Patients who received semaglutide lost 5.4% of their initial weight or roughly 5.2 kg (11.5 pounds), and patients who received placebo lost only 1.2% of their initial weight

The main adverse events were gastrointestinal.
 

‘Exciting data,’ but still early days

“This is very exciting data. It comes from another experienced company with a track record of successful products with a new compound in a class where other related compounds have shown efficacy and safety,” Dan Bessesen, MD, president of The Obesity Society, who was not involved with this research, told this news organization in an email.

“The degree of weight loss is impressive for a 16-week study,” Dr. Bessesen, professor of medicine in the division of endocrinology, metabolism and diabetes at the University of Colorado at Denver, Aurora, added. “The longer-term weight loss will likely be more.”

The side-effect profile is not particularly concerning and is like other drugs in this general class, he said.

However, he also noted a few caveats. This was only a phase 2 study, “so we should not make firm conclusions about efficacy from a study like this, as the number of subjects studied at each dose is relatively small and the follow-up not long.”

In addition, “the dose of semaglutide is the old ‘diabetes’ dose (1 mg) not the weight-loss dose of 2.4 mg or the new diabetes dose of 2 mg. It is not a real comparison with the maximal approved dose of semaglutide. So, we cannot say that it will be better than semaglutide.”

The next hurdle is the “need to see phase 3 studies in a larger group of patients studied for a longer time. Then [the company] will need FDA approval, so it may be a bit of time” before this drug potentially enters the marketplace.

The “bottom line” is that this potential new antiobesity/diabetes drug is “very promising, but [it is] still a little early to say where it ultimately will go.”
 

A1c results presented at EASD

To be included in this study, patients had to be 18-75 years old, have type 2 diabetes, a body mass index of 25-50 kg/m², and hemoglobin A1c of 7%-10%, and be stable on metformin therapy.

The patients had a mean age of 57 years, and 57% were men. They had a mean A1c of 8.1%, a mean BMI of 34 kg/m², and a mean waist circumference of 110 cm (43 inches).

“We just recently reported at the EASD conference last month, the effect of BI 456906 on A1c lowering,” Dr. Rosenstock said.

“It looks like the [drop in] A1c plateaus at 1.9%, which is pretty good when you consider the baseline A1c is around 8%. You get down to around 6%, which is what we regard as a very robust reduction in people with type 2 diabetes on metformin.”

The current analysis showed that patients who received doses of 0.3, 0.9, 1.8, and 2.7 mg/week of the novel drug lost 1.9%, 4.4%, 6.6%, and 6.7% of their initial body weight, respectively, after 16 weeks.

The patients who received 1.2 mg and 1.8 mg twice weekly lost even more weight, 7.2% and 9% of their initial weight, respectively.

At the highest dose, on average, patients lost 13 cm (5 inches) around their waist.

Adverse events were reported by 78% of the patients, most commonly nausea (34% of patients), vomiting (18%), and diarrhea (16%).

Only 1.3% of patients had a drug-related serious adverse event. A total of 16% of patients discontinued the therapy.

Most of the “gastrointestinal adverse events leading the treatment discontinuation were possibly dose and titration related,” Dr. Rosenstock said, “and it’s highly conceivable that for future studies a slower dose escalation may mitigate the occurrence of the gastrointestinal adverse events.”

BI 456906 was coinvented with Zealand Pharma. Under the licensing agreement, Boehringer Ingelheim funds all research, development, and commercialization.

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

SAN DIEGO – A novel glucagonlike peptide-1 (GLP-1)/glucagon dual-receptor agonist, BI 456906, being developed by Boehringer Ingelheim and Zealand Pharma, led to “impressive” weight loss in a phase 2 dosing study of patients with overweight/obesity and type 2 diabetes – but this is early research.

Julio Rosenstock, MD, presented the study results, including weight loss and adverse events, at the annual meeting of the Obesity Society.

At the highest tested dose (1.8 mg twice weekly subcutaneous injections), 57% of patients lost at least 5% of their initial body weight and 35% lost at least 10% of their initial body weight at 16 weeks.

In contrast, among the patients who received a 1-mg semaglutide dose as a comparator, 38% lost at least 5% of their initial body weight and 16% lost at least 10% of their initial body weight at study end.

Sara Freeman/MDedge News

This is “very promising data as an anti-obesity compound,” said Dr. Rosenstock, professor of medicine, University of Texas Southwestern Medical Center in Dallas.

The researchers enrolled 411 adults and randomized them into eight groups of roughly 50 patients each.

They compared six doses of BI 456906 (from 0.3 mg/week to 1.8 mg twice weekly) versus 1 mg/week of the GLP-1 agonist semaglutide (Wegovy, Novo Nordisk) versus placebo.

Patients had a mean initial weight of 97 kg (214 pounds).

After 4 months, on average, patients who received the highest tested dose of BI 456906 lost 9% of their initial weight or roughly 8.7 kg (19 pounds).

Patients who received semaglutide lost 5.4% of their initial weight or roughly 5.2 kg (11.5 pounds), and patients who received placebo lost only 1.2% of their initial weight

The main adverse events were gastrointestinal.
 

‘Exciting data,’ but still early days

“This is very exciting data. It comes from another experienced company with a track record of successful products with a new compound in a class where other related compounds have shown efficacy and safety,” Dan Bessesen, MD, president of The Obesity Society, who was not involved with this research, told this news organization in an email.

“The degree of weight loss is impressive for a 16-week study,” Dr. Bessesen, professor of medicine in the division of endocrinology, metabolism and diabetes at the University of Colorado at Denver, Aurora, added. “The longer-term weight loss will likely be more.”

The side-effect profile is not particularly concerning and is like other drugs in this general class, he said.

However, he also noted a few caveats. This was only a phase 2 study, “so we should not make firm conclusions about efficacy from a study like this, as the number of subjects studied at each dose is relatively small and the follow-up not long.”

In addition, “the dose of semaglutide is the old ‘diabetes’ dose (1 mg) not the weight-loss dose of 2.4 mg or the new diabetes dose of 2 mg. It is not a real comparison with the maximal approved dose of semaglutide. So, we cannot say that it will be better than semaglutide.”

The next hurdle is the “need to see phase 3 studies in a larger group of patients studied for a longer time. Then [the company] will need FDA approval, so it may be a bit of time” before this drug potentially enters the marketplace.

The “bottom line” is that this potential new antiobesity/diabetes drug is “very promising, but [it is] still a little early to say where it ultimately will go.”
 

A1c results presented at EASD

To be included in this study, patients had to be 18-75 years old, have type 2 diabetes, a body mass index of 25-50 kg/m², and hemoglobin A1c of 7%-10%, and be stable on metformin therapy.

The patients had a mean age of 57 years, and 57% were men. They had a mean A1c of 8.1%, a mean BMI of 34 kg/m², and a mean waist circumference of 110 cm (43 inches).

“We just recently reported at the EASD conference last month, the effect of BI 456906 on A1c lowering,” Dr. Rosenstock said.

“It looks like the [drop in] A1c plateaus at 1.9%, which is pretty good when you consider the baseline A1c is around 8%. You get down to around 6%, which is what we regard as a very robust reduction in people with type 2 diabetes on metformin.”

The current analysis showed that patients who received doses of 0.3, 0.9, 1.8, and 2.7 mg/week of the novel drug lost 1.9%, 4.4%, 6.6%, and 6.7% of their initial body weight, respectively, after 16 weeks.

The patients who received 1.2 mg and 1.8 mg twice weekly lost even more weight, 7.2% and 9% of their initial weight, respectively.

At the highest dose, on average, patients lost 13 cm (5 inches) around their waist.

Adverse events were reported by 78% of the patients, most commonly nausea (34% of patients), vomiting (18%), and diarrhea (16%).

Only 1.3% of patients had a drug-related serious adverse event. A total of 16% of patients discontinued the therapy.

Most of the “gastrointestinal adverse events leading the treatment discontinuation were possibly dose and titration related,” Dr. Rosenstock said, “and it’s highly conceivable that for future studies a slower dose escalation may mitigate the occurrence of the gastrointestinal adverse events.”

BI 456906 was coinvented with Zealand Pharma. Under the licensing agreement, Boehringer Ingelheim funds all research, development, and commercialization.

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

SAN DIEGO – Weight loss with tirzepatide was fairly uniform across different body mass index ranges, ages, and number of obesity-related comorbidities in patients with overweight/obesity without type 2 diabetes.

These were the main findings in a session about tirzepatide – the dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) agonist – for obesity, presented at the annual meeting of the Obesity Society.

In May, tirzepatide (Mounjaro), a once-weekly subcutaneous injection, was approved by the Food and Drug Administration for glycemic control in patients with type 2 diabetes based on the SURPASS clinical trials.

Then in June, at the American Diabetes Association 2022 annual meeting, researchers reported “unprecedented” weight loss with tirzepatide in patients without type 2 diabetes, in the phase 3 SURMOUNT-1 clinical trial.

In early October, the FDA granted fast track status (expedited review) to tirzepatide for use as an antiobesity drug.

Now these new analyses from SURMOUNT-1 show that “regardless of BMI, regardless of age, regardless of number of obesity-related complications, there was a clear dose-related weight loss that was pretty consistent across groups,” Session Chair Patrick M. O’Neil, PhD, who was not involved with this research, summarized.

“The absolute levels of these weight losses are higher than we’ve seen thus far with [antiobesity] medications,” added Dr. O’Neil, professor of psychiatry and behavioral sciences and director of the Weight Management Center at the Medical University of South Carolina, Charleston.

“Semaglutide took things up one big notch, and this is up a little notch above that,” he said in an interview.

“I’m a psychologist. It should be remembered that in all cases, the FDA approvals are predicated to using [drugs] as an adjunct to diet and exercise change as well,” he stressed.

“I don’t think people should expect that any medication that is currently available will have a lasting effect when it’s no longer taken,” he continued.

“We don’t expect any of these [antiobesity] medications to be making any permanent physiological changes,” Dr. O’Neil added, but patients could “use this medication to help themselves make some long-lasting behavioral changes, so that when they come off the medication, hopefully they’ll be able to continue these new patterns.

“Clearly the medications are having a significant impact,” he emphasized.
 

BMI, age, comorbidity subgroups, and overall QoL in SURMOUNT-1

SURMOUNT-1 compared the efficacy and safety of tirzepatide 5, 10, and 15 mg subcutaneous once-weekly to placebo, as an adjunct to a reduced-calorie diet and increased physical activity. The study included 2,539 adults without type 2 diabetes who had obesity (BMI ≥ 30 kg/m²) or overweight (BMI ≥ 27 kg/m²) with at least one obesity-related complication (hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease).

Age subgroups

Robert F. Kushner, MD, of Northwestern University, Chicago, noted that “Excessive lean mass loss is a clinical concern in elderly individuals being treated for obesity,” so it’s important to know if weight loss with tirzepatide differs by age.

The researchers performed a post hoc analysis in patients who had dual-energy x-ray absorptiometry (DXA) readings at baseline and week 72 (oral abstract 109).

The three age groups in the current analysis were < 50 years old (99 patients), ≥ 50 to < 65 years old (41 patients), and ≥ 65 years old (20 patients). Overall, 63% of patients were age < 50 years, 31% were age 50 to < 65 years, and 6% were ≥ 65 years.

At 72 weeks, patients taking 5, 10, and 15 mg/week tirzepatide lost 21.5%, 20.8%, and 22% of their initial body weight, respectively.

“Tirzepatide significantly lowered total body mass versus placebo regardless of age subgroups,” and it “consistently lowered fat mass, lean mass, fat-mass-to-lean-mass ratio, and visceral fat mass across age subgroups,” Dr. Kushner reported.
 

BMI subgroups

Louis J. Aronne, MD, Weill Cornell Medicine, New York, presented findings from a prespecified analysis of BMI subgroups (oral abstract 110).

The four BMI subgroups were:

• ≥ 27 to < 30 kg/m² (overweight), mean initial weight 178 pounds, mean weight reduction 29-30 pounds
• ≥ 30 to < 35 kg/m² (class 1 obesity), mean initial weight 198 pounds, mean weight reduction 33-43 pounds
• 35 to < 40 kg/m² (class 2 obesity), mean initial weight 228 pounds, mean reduction 34-56 pounds
• 40 kg/m² (class 3 obesity), mean initial weight 280 pounds, mean weight reduction 44-64 pounds

Patients with an initial BMI of ≥ 35 to < 40 kg/m² who received the 15-mg/week dose of tirzepatide had the greatest weight loss, at 24.5%, which is approximately what is seen with bariatric surgeries such as sleeve gastrectomy (25%).

The proportion of patients reaching ≥ 5% weight reduction was approximately 90% in all weight categories. “These numbers are unprecedented,” said Dr. Aronne.

In addition, overall, 73%-90% of patients receiving the 5- to 15-mg doses of tirzepatide achieved ≥ 10% body weight reduction, and “something we never thought we would see” is that 50%-78% of the patients receiving the drug lost 15% or more of their body weight.

In reply to an audience question, Dr. Aronne said it would take further study to determine who would respond well to tirzepatide.

And in reply to another question about whether it would make sense to treat to a target of a normal BMI, he said: “I think we are getting there.”

Patients in the 27- to 30-kg/m² BMI category lost about the same amount of weight at a 5-mg dose as at a higher dose, suggesting they should stick to the lower dose, which would likely also have fewer side effects, he noted.
 

Number of comorbidities

Comorbidities in SURMOUNT-1 included hypertension, dyslipidemia, obstructive sleep apnea, atherosclerotic cardiovascular disease, osteoarthritis, anxiety/depression, polycystic ovary syndrome, nonalcoholic fatty liver disease, and asthma/chronic obstructive pulmonary disease. Of the patients with no comorbidities, 32.6% had prediabetes (oral abstract 111).

Sriram Machineni, MD, University of North Carolina at Chapel Hill, noted that obesity is associated with a significantly increased risk of clustering of at least two obesity-related complications, but little is known about how this affects outcomes. 

The patients in SURMOUNT-1 were classified into three groups based on number of comorbidities:

• Zero comorbidities, 37% of patients: baseline mean age of 39, mean duration of obesity of 12 years, 29% men
• One comorbidity, 27% of patients: baseline mean age of 44, mean duration of obesity of 14 years, 31% men
• Two or more comorbidities, 36% of patients: baseline mean age of 52, duration of obesity 17 years, 37% men

Regardless of the number of comorbidities, all doses of tirzepatide resulted in a greater reduction in body weight compared with placebo.
 

Quality of life

Jiat Ling Poon, MD, an employee of Eli Lilly, presented findings from patient-reported replies to questionnaires including Impact of Weight on Quality of Life–Lite (IWQOL-Lite), which assesses physical and psychosocial health, and the Short Form–36 Health Survey, which assesses physical functioning, bodily pain, vitality, role-emotional, role-physical, general health, social functioning, and mental health (oral abstract 112).

Tirzepatide at all doses resulted in significantly greater improvements in patient-reported outcomes compared with placebo.

Meanwhile, the phase 3 SURMOUNT-2 clinical trial of tirzepatide for weight loss in patients with type 2 diabetes is projected to be completed in April 2023.  

The studies were funded by Eli Lilly.

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


SAN DIEGO – Weight loss with tirzepatide was fairly uniform across different body mass index ranges, ages, and number of obesity-related comorbidities in patients with overweight/obesity without type 2 diabetes.

These were the main findings in a session about tirzepatide – the dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) agonist – for obesity, presented at the annual meeting of the Obesity Society.

In May, tirzepatide (Mounjaro), a once-weekly subcutaneous injection, was approved by the Food and Drug Administration for glycemic control in patients with type 2 diabetes based on the SURPASS clinical trials.

Then in June, at the American Diabetes Association 2022 annual meeting, researchers reported “unprecedented” weight loss with tirzepatide in patients without type 2 diabetes, in the phase 3 SURMOUNT-1 clinical trial.

In early October, the FDA granted fast track status (expedited review) to tirzepatide for use as an antiobesity drug.

Now these new analyses from SURMOUNT-1 show that “regardless of BMI, regardless of age, regardless of number of obesity-related complications, there was a clear dose-related weight loss that was pretty consistent across groups,” Session Chair Patrick M. O’Neil, PhD, who was not involved with this research, summarized.

“The absolute levels of these weight losses are higher than we’ve seen thus far with [antiobesity] medications,” added Dr. O’Neil, professor of psychiatry and behavioral sciences and director of the Weight Management Center at the Medical University of South Carolina, Charleston.

“Semaglutide took things up one big notch, and this is up a little notch above that,” he said in an interview.

“I’m a psychologist. It should be remembered that in all cases, the FDA approvals are predicated to using [drugs] as an adjunct to diet and exercise change as well,” he stressed.

“I don’t think people should expect that any medication that is currently available will have a lasting effect when it’s no longer taken,” he continued.

“We don’t expect any of these [antiobesity] medications to be making any permanent physiological changes,” Dr. O’Neil added, but patients could “use this medication to help themselves make some long-lasting behavioral changes, so that when they come off the medication, hopefully they’ll be able to continue these new patterns.

“Clearly the medications are having a significant impact,” he emphasized.
 

BMI, age, comorbidity subgroups, and overall QoL in SURMOUNT-1

SURMOUNT-1 compared the efficacy and safety of tirzepatide 5, 10, and 15 mg subcutaneous once-weekly to placebo, as an adjunct to a reduced-calorie diet and increased physical activity. The study included 2,539 adults without type 2 diabetes who had obesity (BMI ≥ 30 kg/m²) or overweight (BMI ≥ 27 kg/m²) with at least one obesity-related complication (hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease).

Age subgroups

Robert F. Kushner, MD, of Northwestern University, Chicago, noted that “Excessive lean mass loss is a clinical concern in elderly individuals being treated for obesity,” so it’s important to know if weight loss with tirzepatide differs by age.

The researchers performed a post hoc analysis in patients who had dual-energy x-ray absorptiometry (DXA) readings at baseline and week 72 (oral abstract 109).

The three age groups in the current analysis were < 50 years old (99 patients), ≥ 50 to < 65 years old (41 patients), and ≥ 65 years old (20 patients). Overall, 63% of patients were age < 50 years, 31% were age 50 to < 65 years, and 6% were ≥ 65 years.

At 72 weeks, patients taking 5, 10, and 15 mg/week tirzepatide lost 21.5%, 20.8%, and 22% of their initial body weight, respectively.

“Tirzepatide significantly lowered total body mass versus placebo regardless of age subgroups,” and it “consistently lowered fat mass, lean mass, fat-mass-to-lean-mass ratio, and visceral fat mass across age subgroups,” Dr. Kushner reported.
 

BMI subgroups

Louis J. Aronne, MD, Weill Cornell Medicine, New York, presented findings from a prespecified analysis of BMI subgroups (oral abstract 110).

The four BMI subgroups were:

• ≥ 27 to < 30 kg/m² (overweight), mean initial weight 178 pounds, mean weight reduction 29-30 pounds
• ≥ 30 to < 35 kg/m² (class 1 obesity), mean initial weight 198 pounds, mean weight reduction 33-43 pounds
• 35 to < 40 kg/m² (class 2 obesity), mean initial weight 228 pounds, mean reduction 34-56 pounds
• 40 kg/m² (class 3 obesity), mean initial weight 280 pounds, mean weight reduction 44-64 pounds

Patients with an initial BMI of ≥ 35 to < 40 kg/m² who received the 15-mg/week dose of tirzepatide had the greatest weight loss, at 24.5%, which is approximately what is seen with bariatric surgeries such as sleeve gastrectomy (25%).

The proportion of patients reaching ≥ 5% weight reduction was approximately 90% in all weight categories. “These numbers are unprecedented,” said Dr. Aronne.

In addition, overall, 73%-90% of patients receiving the 5- to 15-mg doses of tirzepatide achieved ≥ 10% body weight reduction, and “something we never thought we would see” is that 50%-78% of the patients receiving the drug lost 15% or more of their body weight.

In reply to an audience question, Dr. Aronne said it would take further study to determine who would respond well to tirzepatide.

And in reply to another question about whether it would make sense to treat to a target of a normal BMI, he said: “I think we are getting there.”

Patients in the 27- to 30-kg/m² BMI category lost about the same amount of weight at a 5-mg dose as at a higher dose, suggesting they should stick to the lower dose, which would likely also have fewer side effects, he noted.
 

Number of comorbidities

Comorbidities in SURMOUNT-1 included hypertension, dyslipidemia, obstructive sleep apnea, atherosclerotic cardiovascular disease, osteoarthritis, anxiety/depression, polycystic ovary syndrome, nonalcoholic fatty liver disease, and asthma/chronic obstructive pulmonary disease. Of the patients with no comorbidities, 32.6% had prediabetes (oral abstract 111).

Sriram Machineni, MD, University of North Carolina at Chapel Hill, noted that obesity is associated with a significantly increased risk of clustering of at least two obesity-related complications, but little is known about how this affects outcomes. 

The patients in SURMOUNT-1 were classified into three groups based on number of comorbidities:

• Zero comorbidities, 37% of patients: baseline mean age of 39, mean duration of obesity of 12 years, 29% men
• One comorbidity, 27% of patients: baseline mean age of 44, mean duration of obesity of 14 years, 31% men
• Two or more comorbidities, 36% of patients: baseline mean age of 52, duration of obesity 17 years, 37% men

Regardless of the number of comorbidities, all doses of tirzepatide resulted in a greater reduction in body weight compared with placebo.
 

Quality of life

Jiat Ling Poon, MD, an employee of Eli Lilly, presented findings from patient-reported replies to questionnaires including Impact of Weight on Quality of Life–Lite (IWQOL-Lite), which assesses physical and psychosocial health, and the Short Form–36 Health Survey, which assesses physical functioning, bodily pain, vitality, role-emotional, role-physical, general health, social functioning, and mental health (oral abstract 112).

Tirzepatide at all doses resulted in significantly greater improvements in patient-reported outcomes compared with placebo.

Meanwhile, the phase 3 SURMOUNT-2 clinical trial of tirzepatide for weight loss in patients with type 2 diabetes is projected to be completed in April 2023.  

The studies were funded by Eli Lilly.

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


SAN DIEGO – Weight loss with tirzepatide was fairly uniform across different body mass index ranges, ages, and number of obesity-related comorbidities in patients with overweight/obesity without type 2 diabetes.

These were the main findings in a session about tirzepatide – the dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) agonist – for obesity, presented at the annual meeting of the Obesity Society.

In May, tirzepatide (Mounjaro), a once-weekly subcutaneous injection, was approved by the Food and Drug Administration for glycemic control in patients with type 2 diabetes based on the SURPASS clinical trials.

Then in June, at the American Diabetes Association 2022 annual meeting, researchers reported “unprecedented” weight loss with tirzepatide in patients without type 2 diabetes, in the phase 3 SURMOUNT-1 clinical trial.

In early October, the FDA granted fast track status (expedited review) to tirzepatide for use as an antiobesity drug.

Now these new analyses from SURMOUNT-1 show that “regardless of BMI, regardless of age, regardless of number of obesity-related complications, there was a clear dose-related weight loss that was pretty consistent across groups,” Session Chair Patrick M. O’Neil, PhD, who was not involved with this research, summarized.

“The absolute levels of these weight losses are higher than we’ve seen thus far with [antiobesity] medications,” added Dr. O’Neil, professor of psychiatry and behavioral sciences and director of the Weight Management Center at the Medical University of South Carolina, Charleston.

“Semaglutide took things up one big notch, and this is up a little notch above that,” he said in an interview.

“I’m a psychologist. It should be remembered that in all cases, the FDA approvals are predicated to using [drugs] as an adjunct to diet and exercise change as well,” he stressed.

“I don’t think people should expect that any medication that is currently available will have a lasting effect when it’s no longer taken,” he continued.

“We don’t expect any of these [antiobesity] medications to be making any permanent physiological changes,” Dr. O’Neil added, but patients could “use this medication to help themselves make some long-lasting behavioral changes, so that when they come off the medication, hopefully they’ll be able to continue these new patterns.

“Clearly the medications are having a significant impact,” he emphasized.
 

BMI, age, comorbidity subgroups, and overall QoL in SURMOUNT-1

SURMOUNT-1 compared the efficacy and safety of tirzepatide 5, 10, and 15 mg subcutaneous once-weekly to placebo, as an adjunct to a reduced-calorie diet and increased physical activity. The study included 2,539 adults without type 2 diabetes who had obesity (BMI ≥ 30 kg/m²) or overweight (BMI ≥ 27 kg/m²) with at least one obesity-related complication (hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease).

Age subgroups

Robert F. Kushner, MD, of Northwestern University, Chicago, noted that “Excessive lean mass loss is a clinical concern in elderly individuals being treated for obesity,” so it’s important to know if weight loss with tirzepatide differs by age.

The researchers performed a post hoc analysis in patients who had dual-energy x-ray absorptiometry (DXA) readings at baseline and week 72 (oral abstract 109).

The three age groups in the current analysis were < 50 years old (99 patients), ≥ 50 to < 65 years old (41 patients), and ≥ 65 years old (20 patients). Overall, 63% of patients were age < 50 years, 31% were age 50 to < 65 years, and 6% were ≥ 65 years.

At 72 weeks, patients taking 5, 10, and 15 mg/week tirzepatide lost 21.5%, 20.8%, and 22% of their initial body weight, respectively.

“Tirzepatide significantly lowered total body mass versus placebo regardless of age subgroups,” and it “consistently lowered fat mass, lean mass, fat-mass-to-lean-mass ratio, and visceral fat mass across age subgroups,” Dr. Kushner reported.
 

BMI subgroups

Louis J. Aronne, MD, Weill Cornell Medicine, New York, presented findings from a prespecified analysis of BMI subgroups (oral abstract 110).

The four BMI subgroups were:

• ≥ 27 to < 30 kg/m² (overweight), mean initial weight 178 pounds, mean weight reduction 29-30 pounds
• ≥ 30 to < 35 kg/m² (class 1 obesity), mean initial weight 198 pounds, mean weight reduction 33-43 pounds
• 35 to < 40 kg/m² (class 2 obesity), mean initial weight 228 pounds, mean reduction 34-56 pounds
• 40 kg/m² (class 3 obesity), mean initial weight 280 pounds, mean weight reduction 44-64 pounds

Patients with an initial BMI of ≥ 35 to < 40 kg/m² who received the 15-mg/week dose of tirzepatide had the greatest weight loss, at 24.5%, which is approximately what is seen with bariatric surgeries such as sleeve gastrectomy (25%).

The proportion of patients reaching ≥ 5% weight reduction was approximately 90% in all weight categories. “These numbers are unprecedented,” said Dr. Aronne.

In addition, overall, 73%-90% of patients receiving the 5- to 15-mg doses of tirzepatide achieved ≥ 10% body weight reduction, and “something we never thought we would see” is that 50%-78% of the patients receiving the drug lost 15% or more of their body weight.

In reply to an audience question, Dr. Aronne said it would take further study to determine who would respond well to tirzepatide.

And in reply to another question about whether it would make sense to treat to a target of a normal BMI, he said: “I think we are getting there.”

Patients in the 27- to 30-kg/m² BMI category lost about the same amount of weight at a 5-mg dose as at a higher dose, suggesting they should stick to the lower dose, which would likely also have fewer side effects, he noted.
 

Number of comorbidities

Comorbidities in SURMOUNT-1 included hypertension, dyslipidemia, obstructive sleep apnea, atherosclerotic cardiovascular disease, osteoarthritis, anxiety/depression, polycystic ovary syndrome, nonalcoholic fatty liver disease, and asthma/chronic obstructive pulmonary disease. Of the patients with no comorbidities, 32.6% had prediabetes (oral abstract 111).

Sriram Machineni, MD, University of North Carolina at Chapel Hill, noted that obesity is associated with a significantly increased risk of clustering of at least two obesity-related complications, but little is known about how this affects outcomes. 

The patients in SURMOUNT-1 were classified into three groups based on number of comorbidities:

• Zero comorbidities, 37% of patients: baseline mean age of 39, mean duration of obesity of 12 years, 29% men
• One comorbidity, 27% of patients: baseline mean age of 44, mean duration of obesity of 14 years, 31% men
• Two or more comorbidities, 36% of patients: baseline mean age of 52, duration of obesity 17 years, 37% men

Regardless of the number of comorbidities, all doses of tirzepatide resulted in a greater reduction in body weight compared with placebo.
 

Quality of life

Jiat Ling Poon, MD, an employee of Eli Lilly, presented findings from patient-reported replies to questionnaires including Impact of Weight on Quality of Life–Lite (IWQOL-Lite), which assesses physical and psychosocial health, and the Short Form–36 Health Survey, which assesses physical functioning, bodily pain, vitality, role-emotional, role-physical, general health, social functioning, and mental health (oral abstract 112).

Tirzepatide at all doses resulted in significantly greater improvements in patient-reported outcomes compared with placebo.

Meanwhile, the phase 3 SURMOUNT-2 clinical trial of tirzepatide for weight loss in patients with type 2 diabetes is projected to be completed in April 2023.  

The studies were funded by Eli Lilly.

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


Who watches the ED staff?

We heard a really great joke recently, one we simply have to share.

A man in Seattle went to a therapist. “I’m depressed,” he says. “Depressed, overworked, and lonely.”

Chinnapong/iStock/Getty Images

“Oh dear, that sounds quite serious,” the therapist replies. “Tell me all about it.”

“Life just seems so harsh and cruel,” the man explains. “The pandemic has caused 300,000 health care workers across the country to leave the industry.”

“Such as the doctor typically filling this role in the joke,” the therapist, who is not licensed to prescribe medicine, nods.

“Exactly! And with so many respiratory viruses circulating and COVID still hanging around, emergency departments all over the country are facing massive backups. People are waiting outside the hospital for hours, hoping a bed will open up. Things got so bad at a hospital near Seattle in October that a nurse called 911 on her own ED. Told the 911 operator to send the fire department to help out, since they were ‘drowning’ and ‘in dire straits.’ They had 45 patients waiting and only five nurses to take care of them.”

“That is quite serious,” the therapist says, scribbling down unseen notes.

“The fire chief did send a crew out, and they cleaned rooms, changed beds, and took vitals for 90 minutes until the crisis passed,” the man says. “But it’s only a matter of time before it happens again. The hospital president said they have 300 open positions, and literally no one has applied to work in the emergency department. Not one person.”

“And how does all this make you feel?” the therapist asks.

“I feel all alone,” the man says. “This world feels so threatening, like no one cares, and I have no idea what will come next. It’s so vague and uncertain.”

“Ah, I think I have a solution for you,” the therapist says. “Go to the emergency department at St. Michael Medical Center in Silverdale, near Seattle. They’ll get your bad mood all settled, and they’ll prescribe you the medicine you need to relax.”

The man bursts into tears. “You don’t understand,” he says. “I am the emergency department at St. Michael Medical Center.”

Good joke. Everybody laugh. Roll on snare drum. Curtains.

Myth buster: Supplements for cholesterol lowering

When it comes to that nasty low-density lipoprotein cholesterol, some people swear by supplements over statins as a holistic approach. Well, we’re busting the myth that those heart-healthy supplements are even effective in comparison.

Sally Kubetin/MDedge News

Which supplements are we talking about? These six are always on sale at the pharmacy: fish oil, cinnamon, garlic, turmeric, plant sterols, and red yeast rice.

In a study presented at the recent American Heart Association scientific sessions, researchers compared these supplements’ effectiveness in lowering LDL cholesterol with low-dose rosuvastatin or placebo among 199 adults aged 40-75 years who didn’t have a personal history of cardiovascular disease.

Participants who took the statin for 28 days had an average of 24% decrease in total cholesterol and a 38% reduction in LDL cholesterol, while 28 days’ worth of the supplements did no better than the placebo in either measure. Compared with placebo, the plant sterols supplement notably lowered HDL cholesterol and the garlic supplement notably increased LDL cholesterol.

Even though there are other studies showing the validity of plant sterols and red yeast rice to lower LDL cholesterol, author Luke J. Laffin, MD, of the Cleveland Clinic noted that this study shows how supplement results can vary and that more research is needed to see the effect they truly have on cholesterol over time.

So, should you stop taking or recommending supplements for heart health or healthy cholesterol levels? Well, we’re not going to come to your house and raid your medicine cabinet, but the authors of this study are definitely not saying that you should rely on them.

Consider this myth mostly busted.
 

COVID dept. of unintended consequences, part 2

The surveillance testing programs conducted in the first year of the pandemic were, in theory, meant to keep everyone safer. Someone, apparently, forgot to explain that to the students of the University of Wyoming and the University of Idaho.

Luis Alvarez/Getty Images

We’re all familiar with the drill: Students at the two schools had to undergo frequent COVID screening to keep the virus from spreading, thereby making everyone safer. Duck your head now, because here comes the unintended consequence.

The students who didn’t get COVID eventually, and perhaps not so surprisingly, “perceived that the mandatory testing policy decreased their risk of contracting COVID-19, and … this perception led to higher participation in COVID-risky events,” Chian Jones Ritten, PhD, and associates said in PNAS Nexus.

They surveyed 757 students from the Univ. of Washington and 517 from the Univ. of Idaho and found that those who were tested more frequently perceived that they were less likely to contract the virus. Those respondents also more frequently attended indoor gatherings, both small and large, and spent more time in restaurants and bars.

The investigators did not mince words: “From a public health standpoint, such behavior is problematic.”

Current parents/participants in the workforce might have other ideas about an appropriate response to COVID.

At this point, we probably should mention that appropriation is the second-most sincere form of flattery.

Who watches the ED staff?

We heard a really great joke recently, one we simply have to share.

A man in Seattle went to a therapist. “I’m depressed,” he says. “Depressed, overworked, and lonely.”

Chinnapong/iStock/Getty Images

“Oh dear, that sounds quite serious,” the therapist replies. “Tell me all about it.”

“Life just seems so harsh and cruel,” the man explains. “The pandemic has caused 300,000 health care workers across the country to leave the industry.”

“Such as the doctor typically filling this role in the joke,” the therapist, who is not licensed to prescribe medicine, nods.

“Exactly! And with so many respiratory viruses circulating and COVID still hanging around, emergency departments all over the country are facing massive backups. People are waiting outside the hospital for hours, hoping a bed will open up. Things got so bad at a hospital near Seattle in October that a nurse called 911 on her own ED. Told the 911 operator to send the fire department to help out, since they were ‘drowning’ and ‘in dire straits.’ They had 45 patients waiting and only five nurses to take care of them.”

“That is quite serious,” the therapist says, scribbling down unseen notes.

“The fire chief did send a crew out, and they cleaned rooms, changed beds, and took vitals for 90 minutes until the crisis passed,” the man says. “But it’s only a matter of time before it happens again. The hospital president said they have 300 open positions, and literally no one has applied to work in the emergency department. Not one person.”

“And how does all this make you feel?” the therapist asks.

“I feel all alone,” the man says. “This world feels so threatening, like no one cares, and I have no idea what will come next. It’s so vague and uncertain.”

“Ah, I think I have a solution for you,” the therapist says. “Go to the emergency department at St. Michael Medical Center in Silverdale, near Seattle. They’ll get your bad mood all settled, and they’ll prescribe you the medicine you need to relax.”

The man bursts into tears. “You don’t understand,” he says. “I am the emergency department at St. Michael Medical Center.”

Good joke. Everybody laugh. Roll on snare drum. Curtains.

Myth buster: Supplements for cholesterol lowering

When it comes to that nasty low-density lipoprotein cholesterol, some people swear by supplements over statins as a holistic approach. Well, we’re busting the myth that those heart-healthy supplements are even effective in comparison.

Sally Kubetin/MDedge News

Which supplements are we talking about? These six are always on sale at the pharmacy: fish oil, cinnamon, garlic, turmeric, plant sterols, and red yeast rice.

In a study presented at the recent American Heart Association scientific sessions, researchers compared these supplements’ effectiveness in lowering LDL cholesterol with low-dose rosuvastatin or placebo among 199 adults aged 40-75 years who didn’t have a personal history of cardiovascular disease.

Participants who took the statin for 28 days had an average of 24% decrease in total cholesterol and a 38% reduction in LDL cholesterol, while 28 days’ worth of the supplements did no better than the placebo in either measure. Compared with placebo, the plant sterols supplement notably lowered HDL cholesterol and the garlic supplement notably increased LDL cholesterol.

Even though there are other studies showing the validity of plant sterols and red yeast rice to lower LDL cholesterol, author Luke J. Laffin, MD, of the Cleveland Clinic noted that this study shows how supplement results can vary and that more research is needed to see the effect they truly have on cholesterol over time.

So, should you stop taking or recommending supplements for heart health or healthy cholesterol levels? Well, we’re not going to come to your house and raid your medicine cabinet, but the authors of this study are definitely not saying that you should rely on them.

Consider this myth mostly busted.
 

COVID dept. of unintended consequences, part 2

The surveillance testing programs conducted in the first year of the pandemic were, in theory, meant to keep everyone safer. Someone, apparently, forgot to explain that to the students of the University of Wyoming and the University of Idaho.

Luis Alvarez/Getty Images

We’re all familiar with the drill: Students at the two schools had to undergo frequent COVID screening to keep the virus from spreading, thereby making everyone safer. Duck your head now, because here comes the unintended consequence.

The students who didn’t get COVID eventually, and perhaps not so surprisingly, “perceived that the mandatory testing policy decreased their risk of contracting COVID-19, and … this perception led to higher participation in COVID-risky events,” Chian Jones Ritten, PhD, and associates said in PNAS Nexus.

They surveyed 757 students from the Univ. of Washington and 517 from the Univ. of Idaho and found that those who were tested more frequently perceived that they were less likely to contract the virus. Those respondents also more frequently attended indoor gatherings, both small and large, and spent more time in restaurants and bars.

The investigators did not mince words: “From a public health standpoint, such behavior is problematic.”

Current parents/participants in the workforce might have other ideas about an appropriate response to COVID.

At this point, we probably should mention that appropriation is the second-most sincere form of flattery.

Who watches the ED staff?

We heard a really great joke recently, one we simply have to share.

A man in Seattle went to a therapist. “I’m depressed,” he says. “Depressed, overworked, and lonely.”

Chinnapong/iStock/Getty Images

“Oh dear, that sounds quite serious,” the therapist replies. “Tell me all about it.”

“Life just seems so harsh and cruel,” the man explains. “The pandemic has caused 300,000 health care workers across the country to leave the industry.”

“Such as the doctor typically filling this role in the joke,” the therapist, who is not licensed to prescribe medicine, nods.

“Exactly! And with so many respiratory viruses circulating and COVID still hanging around, emergency departments all over the country are facing massive backups. People are waiting outside the hospital for hours, hoping a bed will open up. Things got so bad at a hospital near Seattle in October that a nurse called 911 on her own ED. Told the 911 operator to send the fire department to help out, since they were ‘drowning’ and ‘in dire straits.’ They had 45 patients waiting and only five nurses to take care of them.”

“That is quite serious,” the therapist says, scribbling down unseen notes.

“The fire chief did send a crew out, and they cleaned rooms, changed beds, and took vitals for 90 minutes until the crisis passed,” the man says. “But it’s only a matter of time before it happens again. The hospital president said they have 300 open positions, and literally no one has applied to work in the emergency department. Not one person.”

“And how does all this make you feel?” the therapist asks.

“I feel all alone,” the man says. “This world feels so threatening, like no one cares, and I have no idea what will come next. It’s so vague and uncertain.”

“Ah, I think I have a solution for you,” the therapist says. “Go to the emergency department at St. Michael Medical Center in Silverdale, near Seattle. They’ll get your bad mood all settled, and they’ll prescribe you the medicine you need to relax.”

The man bursts into tears. “You don’t understand,” he says. “I am the emergency department at St. Michael Medical Center.”

Good joke. Everybody laugh. Roll on snare drum. Curtains.

Myth buster: Supplements for cholesterol lowering

When it comes to that nasty low-density lipoprotein cholesterol, some people swear by supplements over statins as a holistic approach. Well, we’re busting the myth that those heart-healthy supplements are even effective in comparison.

Sally Kubetin/MDedge News

Which supplements are we talking about? These six are always on sale at the pharmacy: fish oil, cinnamon, garlic, turmeric, plant sterols, and red yeast rice.

In a study presented at the recent American Heart Association scientific sessions, researchers compared these supplements’ effectiveness in lowering LDL cholesterol with low-dose rosuvastatin or placebo among 199 adults aged 40-75 years who didn’t have a personal history of cardiovascular disease.

Participants who took the statin for 28 days had an average of 24% decrease in total cholesterol and a 38% reduction in LDL cholesterol, while 28 days’ worth of the supplements did no better than the placebo in either measure. Compared with placebo, the plant sterols supplement notably lowered HDL cholesterol and the garlic supplement notably increased LDL cholesterol.

Even though there are other studies showing the validity of plant sterols and red yeast rice to lower LDL cholesterol, author Luke J. Laffin, MD, of the Cleveland Clinic noted that this study shows how supplement results can vary and that more research is needed to see the effect they truly have on cholesterol over time.

So, should you stop taking or recommending supplements for heart health or healthy cholesterol levels? Well, we’re not going to come to your house and raid your medicine cabinet, but the authors of this study are definitely not saying that you should rely on them.

Consider this myth mostly busted.
 

COVID dept. of unintended consequences, part 2

The surveillance testing programs conducted in the first year of the pandemic were, in theory, meant to keep everyone safer. Someone, apparently, forgot to explain that to the students of the University of Wyoming and the University of Idaho.

Luis Alvarez/Getty Images

We’re all familiar with the drill: Students at the two schools had to undergo frequent COVID screening to keep the virus from spreading, thereby making everyone safer. Duck your head now, because here comes the unintended consequence.

The students who didn’t get COVID eventually, and perhaps not so surprisingly, “perceived that the mandatory testing policy decreased their risk of contracting COVID-19, and … this perception led to higher participation in COVID-risky events,” Chian Jones Ritten, PhD, and associates said in PNAS Nexus.

They surveyed 757 students from the Univ. of Washington and 517 from the Univ. of Idaho and found that those who were tested more frequently perceived that they were less likely to contract the virus. Those respondents also more frequently attended indoor gatherings, both small and large, and spent more time in restaurants and bars.

The investigators did not mince words: “From a public health standpoint, such behavior is problematic.”

Current parents/participants in the workforce might have other ideas about an appropriate response to COVID.

At this point, we probably should mention that appropriation is the second-most sincere form of flattery.

Use of a combination antihypertensive product containing quarter doses of four different drugs could be an effective strategy to get patients to target blood pressures in one step, a new study suggests. 

The study, QUARTET-USA, showed a reduction in BP of almost 5 mm Hg more than the comparator of one antihypertensive agent at standard dose over the 12-week follow-up period in patients with mild to moderate hypertension.

The QUARTET-USA study was presented at the American Heart Association scientific sessions by Mark Huffman, MD, professor of medicine at Washington University in St. Louis. 

It builds on a previous trial, QUARTET, conducted in Australia, which first showed benefits with this approach.

In the new U.S. study, which was considerably smaller than the Australian trial, the four-drug combination, including candesartan, amlodipine, indapamide, and bisoprolol, led to a –4.8/–4.9 mm Hg greater reduction in BP from baseline to 12 weeks, compared with standard-dose candesartan monotherapy.

Differences in systolic BP were not statistically significant, which is likely because of limited power related to the sample size, Dr. Huffman noted.

Adverse events were more common in the four-drug intervention group, but the rate of discontinuation was higher in the comparator group. No severe adverse events were deemed related to the study drug.

“The direction and magnitude of [the] blood pressure–lowering effect were similar between the previous Australian study and this American study, despite different populations with lower baseline blood pressure in the current study, thus strengthening the case for this new approach,” Dr. Huffman concluded.

“The two studies together show that the approach of using four drugs in quarter doses is more effective in lowering blood pressure than a single standard dose antihypertensive agent and has an acceptable safely profile,” he said in an interview.

He said the four-drug combination could be an effective way of getting patients to target without multiple appointments.

“If you think about how many visits to the doctor’s office it takes to get patients to goal blood pressures, this combination gets patients down to new guideline target levels in one step, whereas in the SPRINT trial it took three or more visits to get down to these levels. And in practice we lose people – they don’t come back,” he said.

Dr. Huffman explained that the rationale for the study was the persistently low hypertension control rate, which demonstrates the need for a new approach.

The previous Australian QUARTET study suggested that ultra–low-dose combination therapy has a favorable balance between blood pressure–lowering effect, tolerability, and adherence.

That study, conducted in 591 patients and reported in 2021, demonstrated a greater BP-lowering effect with a four-drug combination at quarter doses (irbesartan 37.5 mg, amlodipine 1.25 mg, indapamide 0.625 mg, bisoprolol 2.5 mg) at 12 weeks, compared with irbesartan 150 mg daily. Systolic BP was reduced by more than 6.9 mm Hg and diastolic BP by 5.8 mm Hg than full-dose irbesartan alone, both significant differences.

The current study, QUARTET-USA, aimed to see if a similar strategy could produce comparable results in a U.S. population.

The U.S. study included 62 patients from the Access Community Health Network, Chicago, who were either treatment naive with BPs above 140/90 mm Hg, or already taking antihypertensive monotherapy with BPs above 130/85 mm Hg.

The mean systolic BP at baseline was 138 mm Hg and the mean diastolic pressure was 84 mm Hg.

Study participants were mainly from ethnic minorities (90% Hispanic or Black) and over half were from low-income households (annual household income less than $25,000).

They were randomly assigned to daily administration of a four-drug combination at quarter doses (candesartan 2 mg, amlodipine 1.25 mg, indapamide 0.625 mg, bisoprolol 2.5 mg) or a full dose of candesartan 8 mg (the comparator arm).

Amlodipine 5 mg daily could be added on to treatment if BP remained above 130/80 mm Hg at 6 weeks. This occurred in 18% of the study group versus 53% of the comparator group.

Results showed that at 12 weeks the adjusted mean change in systolic BP weeks was –4.8 mm Hg (95% CI,–10.7 to 1.2), and the adjusted mean change in diastolic BP was –4.9 mm Hg (95% CI, –8.6 to –1.1) in the four-drug combination group, compared with the comparator arm.

Average BPs at the end of 12-week study period were 121 mm Hg systolic and 73 mm Hg diastolic in the four-drug intervention group, compared with 124 mm Hg systolic and 77 mm Hg diastolic in the comparator group.

Any adverse events that were possibly related to drug therapy occurred in 25% of the intervention group versus 10% of the comparator group. But adverse events leading to discontinuation occurred in 6.3% of the study group versus 26.7% of patients in the comparator arm.

“New approaches are needed to achieve lower blood pressure targets, especially for patients and communities with a high burden of hypertension and hypertension-related diseases. QUARTET-USA was the first trial of a four-drug, ultra–low-dose, blood pressure–lowering combination therapy in the U.S.,” Dr. Huffman said.

“We showed reductions in blood pressure similar in magnitude to those in the Australian study. It is useful to know that the direction of the effect is similar across varied populations. Now that we have that signal of efficacy and tolerability, we can move to actually getting it into the hands of patients and providers,” he added.

Noting that further studies will be required to attain marketing authorization, Dr. Huffman suggested that a pharmaceutical company would need to complete that process.

“These are promising results for companies who may be interested in partnering,” he said.

‘A more efficient approach’ 

LaPrincess C. Brewer, MD, assistant professor of medicine at the Mayo Clinic, Rochester, Minn., and discussant of the study, said the QUARTET-USA study suggests the four-drug, low-dose combination shows promise in lowering BP, compared with the standard dose, and while the reduction in systolic BP was not quite significant, it was clinically meaningful.

“Most U.S. adults with hypertension do not have it under control. This is due to unfavorable social and structural determinants of health which limit adherence to antihypertensive medication,” Dr. Brewer noted.  

From a patient point of view, the multiple visits needed to attain goals are a burden and there is also the issue of clinical inertia and lack of medication intensification by clinicians, she commented. 

“Of patients with uncontrolled hypertension, 40% are taking just one antihypertensive medication, so up-front, low-dose combination therapy is likely a more efficient approach,” she said.

“This study builds the evidence base for the need for tailored interventions that address the social determinants of health and the intentional prioritization of diverse population in clinical trials,” Dr. Brewer concluded.

QUARTET was an investigator-initiated study, Dr. Huffman reported a pending patent for a heart failure polypill. The George Institute for Global Health, Sydney, Australia, where Huffman has a secondary appointment, has a patent, license, and has received investment funding with intent to commercialize fixed-dose combination therapy. Dr. Brewer reported research support from the National Institutes of Health, Centers for Disease Control and Prevention, American Heart Association, and Bristol-Meyers Squibb Foundation.

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

Use of a combination antihypertensive product containing quarter doses of four different drugs could be an effective strategy to get patients to target blood pressures in one step, a new study suggests. 

The study, QUARTET-USA, showed a reduction in BP of almost 5 mm Hg more than the comparator of one antihypertensive agent at standard dose over the 12-week follow-up period in patients with mild to moderate hypertension.

The QUARTET-USA study was presented at the American Heart Association scientific sessions by Mark Huffman, MD, professor of medicine at Washington University in St. Louis. 

It builds on a previous trial, QUARTET, conducted in Australia, which first showed benefits with this approach.

In the new U.S. study, which was considerably smaller than the Australian trial, the four-drug combination, including candesartan, amlodipine, indapamide, and bisoprolol, led to a –4.8/–4.9 mm Hg greater reduction in BP from baseline to 12 weeks, compared with standard-dose candesartan monotherapy.

Differences in systolic BP were not statistically significant, which is likely because of limited power related to the sample size, Dr. Huffman noted.

Adverse events were more common in the four-drug intervention group, but the rate of discontinuation was higher in the comparator group. No severe adverse events were deemed related to the study drug.

“The direction and magnitude of [the] blood pressure–lowering effect were similar between the previous Australian study and this American study, despite different populations with lower baseline blood pressure in the current study, thus strengthening the case for this new approach,” Dr. Huffman concluded.

“The two studies together show that the approach of using four drugs in quarter doses is more effective in lowering blood pressure than a single standard dose antihypertensive agent and has an acceptable safely profile,” he said in an interview.

He said the four-drug combination could be an effective way of getting patients to target without multiple appointments.

“If you think about how many visits to the doctor’s office it takes to get patients to goal blood pressures, this combination gets patients down to new guideline target levels in one step, whereas in the SPRINT trial it took three or more visits to get down to these levels. And in practice we lose people – they don’t come back,” he said.

Dr. Huffman explained that the rationale for the study was the persistently low hypertension control rate, which demonstrates the need for a new approach.

The previous Australian QUARTET study suggested that ultra–low-dose combination therapy has a favorable balance between blood pressure–lowering effect, tolerability, and adherence.

That study, conducted in 591 patients and reported in 2021, demonstrated a greater BP-lowering effect with a four-drug combination at quarter doses (irbesartan 37.5 mg, amlodipine 1.25 mg, indapamide 0.625 mg, bisoprolol 2.5 mg) at 12 weeks, compared with irbesartan 150 mg daily. Systolic BP was reduced by more than 6.9 mm Hg and diastolic BP by 5.8 mm Hg than full-dose irbesartan alone, both significant differences.

The current study, QUARTET-USA, aimed to see if a similar strategy could produce comparable results in a U.S. population.

The U.S. study included 62 patients from the Access Community Health Network, Chicago, who were either treatment naive with BPs above 140/90 mm Hg, or already taking antihypertensive monotherapy with BPs above 130/85 mm Hg.

The mean systolic BP at baseline was 138 mm Hg and the mean diastolic pressure was 84 mm Hg.

Study participants were mainly from ethnic minorities (90% Hispanic or Black) and over half were from low-income households (annual household income less than $25,000).

They were randomly assigned to daily administration of a four-drug combination at quarter doses (candesartan 2 mg, amlodipine 1.25 mg, indapamide 0.625 mg, bisoprolol 2.5 mg) or a full dose of candesartan 8 mg (the comparator arm).

Amlodipine 5 mg daily could be added on to treatment if BP remained above 130/80 mm Hg at 6 weeks. This occurred in 18% of the study group versus 53% of the comparator group.

Results showed that at 12 weeks the adjusted mean change in systolic BP weeks was –4.8 mm Hg (95% CI,–10.7 to 1.2), and the adjusted mean change in diastolic BP was –4.9 mm Hg (95% CI, –8.6 to –1.1) in the four-drug combination group, compared with the comparator arm.

Average BPs at the end of 12-week study period were 121 mm Hg systolic and 73 mm Hg diastolic in the four-drug intervention group, compared with 124 mm Hg systolic and 77 mm Hg diastolic in the comparator group.

Any adverse events that were possibly related to drug therapy occurred in 25% of the intervention group versus 10% of the comparator group. But adverse events leading to discontinuation occurred in 6.3% of the study group versus 26.7% of patients in the comparator arm.

“New approaches are needed to achieve lower blood pressure targets, especially for patients and communities with a high burden of hypertension and hypertension-related diseases. QUARTET-USA was the first trial of a four-drug, ultra–low-dose, blood pressure–lowering combination therapy in the U.S.,” Dr. Huffman said.

“We showed reductions in blood pressure similar in magnitude to those in the Australian study. It is useful to know that the direction of the effect is similar across varied populations. Now that we have that signal of efficacy and tolerability, we can move to actually getting it into the hands of patients and providers,” he added.

Noting that further studies will be required to attain marketing authorization, Dr. Huffman suggested that a pharmaceutical company would need to complete that process.

“These are promising results for companies who may be interested in partnering,” he said.

‘A more efficient approach’ 

LaPrincess C. Brewer, MD, assistant professor of medicine at the Mayo Clinic, Rochester, Minn., and discussant of the study, said the QUARTET-USA study suggests the four-drug, low-dose combination shows promise in lowering BP, compared with the standard dose, and while the reduction in systolic BP was not quite significant, it was clinically meaningful.

“Most U.S. adults with hypertension do not have it under control. This is due to unfavorable social and structural determinants of health which limit adherence to antihypertensive medication,” Dr. Brewer noted.  

From a patient point of view, the multiple visits needed to attain goals are a burden and there is also the issue of clinical inertia and lack of medication intensification by clinicians, she commented. 

“Of patients with uncontrolled hypertension, 40% are taking just one antihypertensive medication, so up-front, low-dose combination therapy is likely a more efficient approach,” she said.

“This study builds the evidence base for the need for tailored interventions that address the social determinants of health and the intentional prioritization of diverse population in clinical trials,” Dr. Brewer concluded.

QUARTET was an investigator-initiated study, Dr. Huffman reported a pending patent for a heart failure polypill. The George Institute for Global Health, Sydney, Australia, where Huffman has a secondary appointment, has a patent, license, and has received investment funding with intent to commercialize fixed-dose combination therapy. Dr. Brewer reported research support from the National Institutes of Health, Centers for Disease Control and Prevention, American Heart Association, and Bristol-Meyers Squibb Foundation.

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

Use of a combination antihypertensive product containing quarter doses of four different drugs could be an effective strategy to get patients to target blood pressures in one step, a new study suggests. 

The study, QUARTET-USA, showed a reduction in BP of almost 5 mm Hg more than the comparator of one antihypertensive agent at standard dose over the 12-week follow-up period in patients with mild to moderate hypertension.

The QUARTET-USA study was presented at the American Heart Association scientific sessions by Mark Huffman, MD, professor of medicine at Washington University in St. Louis. 

It builds on a previous trial, QUARTET, conducted in Australia, which first showed benefits with this approach.

In the new U.S. study, which was considerably smaller than the Australian trial, the four-drug combination, including candesartan, amlodipine, indapamide, and bisoprolol, led to a –4.8/–4.9 mm Hg greater reduction in BP from baseline to 12 weeks, compared with standard-dose candesartan monotherapy.

Differences in systolic BP were not statistically significant, which is likely because of limited power related to the sample size, Dr. Huffman noted.

Adverse events were more common in the four-drug intervention group, but the rate of discontinuation was higher in the comparator group. No severe adverse events were deemed related to the study drug.

“The direction and magnitude of [the] blood pressure–lowering effect were similar between the previous Australian study and this American study, despite different populations with lower baseline blood pressure in the current study, thus strengthening the case for this new approach,” Dr. Huffman concluded.

“The two studies together show that the approach of using four drugs in quarter doses is more effective in lowering blood pressure than a single standard dose antihypertensive agent and has an acceptable safely profile,” he said in an interview.

He said the four-drug combination could be an effective way of getting patients to target without multiple appointments.

“If you think about how many visits to the doctor’s office it takes to get patients to goal blood pressures, this combination gets patients down to new guideline target levels in one step, whereas in the SPRINT trial it took three or more visits to get down to these levels. And in practice we lose people – they don’t come back,” he said.

Dr. Huffman explained that the rationale for the study was the persistently low hypertension control rate, which demonstrates the need for a new approach.

The previous Australian QUARTET study suggested that ultra–low-dose combination therapy has a favorable balance between blood pressure–lowering effect, tolerability, and adherence.

That study, conducted in 591 patients and reported in 2021, demonstrated a greater BP-lowering effect with a four-drug combination at quarter doses (irbesartan 37.5 mg, amlodipine 1.25 mg, indapamide 0.625 mg, bisoprolol 2.5 mg) at 12 weeks, compared with irbesartan 150 mg daily. Systolic BP was reduced by more than 6.9 mm Hg and diastolic BP by 5.8 mm Hg than full-dose irbesartan alone, both significant differences.

The current study, QUARTET-USA, aimed to see if a similar strategy could produce comparable results in a U.S. population.

The U.S. study included 62 patients from the Access Community Health Network, Chicago, who were either treatment naive with BPs above 140/90 mm Hg, or already taking antihypertensive monotherapy with BPs above 130/85 mm Hg.

The mean systolic BP at baseline was 138 mm Hg and the mean diastolic pressure was 84 mm Hg.

Study participants were mainly from ethnic minorities (90% Hispanic or Black) and over half were from low-income households (annual household income less than $25,000).

They were randomly assigned to daily administration of a four-drug combination at quarter doses (candesartan 2 mg, amlodipine 1.25 mg, indapamide 0.625 mg, bisoprolol 2.5 mg) or a full dose of candesartan 8 mg (the comparator arm).

Amlodipine 5 mg daily could be added on to treatment if BP remained above 130/80 mm Hg at 6 weeks. This occurred in 18% of the study group versus 53% of the comparator group.

Results showed that at 12 weeks the adjusted mean change in systolic BP weeks was –4.8 mm Hg (95% CI,–10.7 to 1.2), and the adjusted mean change in diastolic BP was –4.9 mm Hg (95% CI, –8.6 to –1.1) in the four-drug combination group, compared with the comparator arm.

Average BPs at the end of 12-week study period were 121 mm Hg systolic and 73 mm Hg diastolic in the four-drug intervention group, compared with 124 mm Hg systolic and 77 mm Hg diastolic in the comparator group.

Any adverse events that were possibly related to drug therapy occurred in 25% of the intervention group versus 10% of the comparator group. But adverse events leading to discontinuation occurred in 6.3% of the study group versus 26.7% of patients in the comparator arm.

“New approaches are needed to achieve lower blood pressure targets, especially for patients and communities with a high burden of hypertension and hypertension-related diseases. QUARTET-USA was the first trial of a four-drug, ultra–low-dose, blood pressure–lowering combination therapy in the U.S.,” Dr. Huffman said.

“We showed reductions in blood pressure similar in magnitude to those in the Australian study. It is useful to know that the direction of the effect is similar across varied populations. Now that we have that signal of efficacy and tolerability, we can move to actually getting it into the hands of patients and providers,” he added.

Noting that further studies will be required to attain marketing authorization, Dr. Huffman suggested that a pharmaceutical company would need to complete that process.

“These are promising results for companies who may be interested in partnering,” he said.

‘A more efficient approach’ 

LaPrincess C. Brewer, MD, assistant professor of medicine at the Mayo Clinic, Rochester, Minn., and discussant of the study, said the QUARTET-USA study suggests the four-drug, low-dose combination shows promise in lowering BP, compared with the standard dose, and while the reduction in systolic BP was not quite significant, it was clinically meaningful.

“Most U.S. adults with hypertension do not have it under control. This is due to unfavorable social and structural determinants of health which limit adherence to antihypertensive medication,” Dr. Brewer noted.  

From a patient point of view, the multiple visits needed to attain goals are a burden and there is also the issue of clinical inertia and lack of medication intensification by clinicians, she commented. 

“Of patients with uncontrolled hypertension, 40% are taking just one antihypertensive medication, so up-front, low-dose combination therapy is likely a more efficient approach,” she said.

“This study builds the evidence base for the need for tailored interventions that address the social determinants of health and the intentional prioritization of diverse population in clinical trials,” Dr. Brewer concluded.

QUARTET was an investigator-initiated study, Dr. Huffman reported a pending patent for a heart failure polypill. The George Institute for Global Health, Sydney, Australia, where Huffman has a secondary appointment, has a patent, license, and has received investment funding with intent to commercialize fixed-dose combination therapy. Dr. Brewer reported research support from the National Institutes of Health, Centers for Disease Control and Prevention, American Heart Association, and Bristol-Meyers Squibb Foundation.

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

This year Medscape surveyed more than 2,300 physicians about how they prioritized various social issues. Around half of them rated climate change among their five most important issues. Slightly lower percentages of doctors prioritized domestic violence and immigration/refugee policies that highly, and about 40% did so regarding reproductive rights in the United States.

Survey responses and comments left on the Physicians’ Views on Today’s Divisive Social Issues 2022 report provide insights into doctors’ attitudes and thinking about these four social challenges.
 

Relevance of climate change to health care

In the Medscape report, 61% of physicians described themselves as “very concerned” or “concerned” about climate change, and about 7 in 10 agreed with the statement that it should be a top worldwide priority. “Climate change is the most pressing issue of this century,” a psychiatrist respondent wrote.

What about direct effects on patients’ health? An internist worried that rising temperatures will cause “pathogens to spread and infect disadvantaged people who do not have health access and have immunocompromised conditions.” A family medicine physician predicted “more weather disasters, more asthma, more hormonal changes, and more obesity.”

However, physician viewpoints ran the gamut with an issue that has become politically and emotionally charged. Descriptions such as “overblown,” “hysteria,” “hoax,” and “farce” were used. “Climate change is a natural phenomenon under God’s purview,” an emergency medicine physician said.

And there was some middle-ground thinking. “It’s overstated but quite real,” a pediatrician respondent wrote. Added an ophthalmologist: “It has gone on for ages. We must work to decrease man-made conditions that affect climate change, but it must be done in an intelligent fashion.”
 

Domestic violence: What physicians can do

About 7 in 10 physicians surveyed by Medscape said they don’t think the United States is adequately tackling domestic violence. “It is underrecognized and ignored,” a psychiatrist respondent argued. The problem is “rampant and unacceptable, pushed into a closet and normalized, with associated shame,” an emergency medicine doctor wrote.

Many respondents noted that physicians are under a mandate to report abuse of or a suspicious injury to a patient. Some shared anecdotes about how they reported action they had taken when they suspected it. “I’ve told patients who may be in dangerous situations that I’m a safe person and provide a safe space,” a radiologist added. An internist said, “I’ve recently started to ask about safety at home during triage on every patient.”

Other doctors bemoaned a lack of adequate education on detecting and managing domestic violence and abuse. “Domestic violence is often not recognized by health care providers,” a psychiatrist respondent observed.
 

Expanding legal immigration

In the Medscape report, 34% of physicians felt U.S. immigration/refugee policies need to be tougher, while 28% said they are too restrictive, and about a fifth saw them as appropriate.

“As an immigrant, I can tell you that the system is flawed and needs a complete overhaul, which will take a bipartisan effort,” an endocrinologist respondent wrote.

A number of respondents argued that it’s critical to simplify the process of obtaining U.S. citizenship so that fewer will feel forced to enter the country illegally. “For a country that relies very heavily on immigrants to sustain our health care system, we behave like idiots in denying safe harbor,” a nephrologist asserted.

A neurologist concurred. “Legal immigration needs to be encouraged. It should be easier to exchange visitor or student visa to immigrant visa in order to retain talent in the health care and technology fields, which would alleviate the shortage of workers in health care.”
 

Reproductive rights: No easy answers

Medscape’s survey was conducted before the U.S. Supreme Court in June reversed Roe v. Wade. In the report, 71% of physicians described themselves as very to somewhat concerned about women’s reproductive rights, but their viewpoints became nuanced after that. “There is a big disparity among physicians on this topic,” an oncologist respondent wrote.

At one end of the spectrum, 3% of doctors felt that abortions should never be permitted. “The human baby in the womb is an independent person with the right to life,” a pathologist said. At the other end, nearly one-fourth of physicians believed abortion should be accessible under all circumstances, regardless of trimester or reason. “I am just here to support the woman and make her decision a reality,” an internist said.

While saying an abortion should be granted after “fetal viability” only “in extenuating circumstances,” an ob.gyn. respondent said she is “extremely concerned” about attacks on abortion rights. “Some of us are old enough to remember women coming to the ER in extremis after illegal procedures, prior to Roe v. Wade.”

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

This year Medscape surveyed more than 2,300 physicians about how they prioritized various social issues. Around half of them rated climate change among their five most important issues. Slightly lower percentages of doctors prioritized domestic violence and immigration/refugee policies that highly, and about 40% did so regarding reproductive rights in the United States.

Survey responses and comments left on the Physicians’ Views on Today’s Divisive Social Issues 2022 report provide insights into doctors’ attitudes and thinking about these four social challenges.
 

Relevance of climate change to health care

In the Medscape report, 61% of physicians described themselves as “very concerned” or “concerned” about climate change, and about 7 in 10 agreed with the statement that it should be a top worldwide priority. “Climate change is the most pressing issue of this century,” a psychiatrist respondent wrote.

What about direct effects on patients’ health? An internist worried that rising temperatures will cause “pathogens to spread and infect disadvantaged people who do not have health access and have immunocompromised conditions.” A family medicine physician predicted “more weather disasters, more asthma, more hormonal changes, and more obesity.”

However, physician viewpoints ran the gamut with an issue that has become politically and emotionally charged. Descriptions such as “overblown,” “hysteria,” “hoax,” and “farce” were used. “Climate change is a natural phenomenon under God’s purview,” an emergency medicine physician said.

And there was some middle-ground thinking. “It’s overstated but quite real,” a pediatrician respondent wrote. Added an ophthalmologist: “It has gone on for ages. We must work to decrease man-made conditions that affect climate change, but it must be done in an intelligent fashion.”
 

Domestic violence: What physicians can do

About 7 in 10 physicians surveyed by Medscape said they don’t think the United States is adequately tackling domestic violence. “It is underrecognized and ignored,” a psychiatrist respondent argued. The problem is “rampant and unacceptable, pushed into a closet and normalized, with associated shame,” an emergency medicine doctor wrote.

Many respondents noted that physicians are under a mandate to report abuse of or a suspicious injury to a patient. Some shared anecdotes about how they reported action they had taken when they suspected it. “I’ve told patients who may be in dangerous situations that I’m a safe person and provide a safe space,” a radiologist added. An internist said, “I’ve recently started to ask about safety at home during triage on every patient.”

Other doctors bemoaned a lack of adequate education on detecting and managing domestic violence and abuse. “Domestic violence is often not recognized by health care providers,” a psychiatrist respondent observed.
 

Expanding legal immigration

In the Medscape report, 34% of physicians felt U.S. immigration/refugee policies need to be tougher, while 28% said they are too restrictive, and about a fifth saw them as appropriate.

“As an immigrant, I can tell you that the system is flawed and needs a complete overhaul, which will take a bipartisan effort,” an endocrinologist respondent wrote.

A number of respondents argued that it’s critical to simplify the process of obtaining U.S. citizenship so that fewer will feel forced to enter the country illegally. “For a country that relies very heavily on immigrants to sustain our health care system, we behave like idiots in denying safe harbor,” a nephrologist asserted.

A neurologist concurred. “Legal immigration needs to be encouraged. It should be easier to exchange visitor or student visa to immigrant visa in order to retain talent in the health care and technology fields, which would alleviate the shortage of workers in health care.”
 

Reproductive rights: No easy answers

Medscape’s survey was conducted before the U.S. Supreme Court in June reversed Roe v. Wade. In the report, 71% of physicians described themselves as very to somewhat concerned about women’s reproductive rights, but their viewpoints became nuanced after that. “There is a big disparity among physicians on this topic,” an oncologist respondent wrote.

At one end of the spectrum, 3% of doctors felt that abortions should never be permitted. “The human baby in the womb is an independent person with the right to life,” a pathologist said. At the other end, nearly one-fourth of physicians believed abortion should be accessible under all circumstances, regardless of trimester or reason. “I am just here to support the woman and make her decision a reality,” an internist said.

While saying an abortion should be granted after “fetal viability” only “in extenuating circumstances,” an ob.gyn. respondent said she is “extremely concerned” about attacks on abortion rights. “Some of us are old enough to remember women coming to the ER in extremis after illegal procedures, prior to Roe v. Wade.”

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

This year Medscape surveyed more than 2,300 physicians about how they prioritized various social issues. Around half of them rated climate change among their five most important issues. Slightly lower percentages of doctors prioritized domestic violence and immigration/refugee policies that highly, and about 40% did so regarding reproductive rights in the United States.

Survey responses and comments left on the Physicians’ Views on Today’s Divisive Social Issues 2022 report provide insights into doctors’ attitudes and thinking about these four social challenges.
 

Relevance of climate change to health care

In the Medscape report, 61% of physicians described themselves as “very concerned” or “concerned” about climate change, and about 7 in 10 agreed with the statement that it should be a top worldwide priority. “Climate change is the most pressing issue of this century,” a psychiatrist respondent wrote.

What about direct effects on patients’ health? An internist worried that rising temperatures will cause “pathogens to spread and infect disadvantaged people who do not have health access and have immunocompromised conditions.” A family medicine physician predicted “more weather disasters, more asthma, more hormonal changes, and more obesity.”

However, physician viewpoints ran the gamut with an issue that has become politically and emotionally charged. Descriptions such as “overblown,” “hysteria,” “hoax,” and “farce” were used. “Climate change is a natural phenomenon under God’s purview,” an emergency medicine physician said.

And there was some middle-ground thinking. “It’s overstated but quite real,” a pediatrician respondent wrote. Added an ophthalmologist: “It has gone on for ages. We must work to decrease man-made conditions that affect climate change, but it must be done in an intelligent fashion.”
 

Domestic violence: What physicians can do

About 7 in 10 physicians surveyed by Medscape said they don’t think the United States is adequately tackling domestic violence. “It is underrecognized and ignored,” a psychiatrist respondent argued. The problem is “rampant and unacceptable, pushed into a closet and normalized, with associated shame,” an emergency medicine doctor wrote.

Many respondents noted that physicians are under a mandate to report abuse of or a suspicious injury to a patient. Some shared anecdotes about how they reported action they had taken when they suspected it. “I’ve told patients who may be in dangerous situations that I’m a safe person and provide a safe space,” a radiologist added. An internist said, “I’ve recently started to ask about safety at home during triage on every patient.”

Other doctors bemoaned a lack of adequate education on detecting and managing domestic violence and abuse. “Domestic violence is often not recognized by health care providers,” a psychiatrist respondent observed.
 

Expanding legal immigration

In the Medscape report, 34% of physicians felt U.S. immigration/refugee policies need to be tougher, while 28% said they are too restrictive, and about a fifth saw them as appropriate.

“As an immigrant, I can tell you that the system is flawed and needs a complete overhaul, which will take a bipartisan effort,” an endocrinologist respondent wrote.

A number of respondents argued that it’s critical to simplify the process of obtaining U.S. citizenship so that fewer will feel forced to enter the country illegally. “For a country that relies very heavily on immigrants to sustain our health care system, we behave like idiots in denying safe harbor,” a nephrologist asserted.

A neurologist concurred. “Legal immigration needs to be encouraged. It should be easier to exchange visitor or student visa to immigrant visa in order to retain talent in the health care and technology fields, which would alleviate the shortage of workers in health care.”
 

Reproductive rights: No easy answers

Medscape’s survey was conducted before the U.S. Supreme Court in June reversed Roe v. Wade. In the report, 71% of physicians described themselves as very to somewhat concerned about women’s reproductive rights, but their viewpoints became nuanced after that. “There is a big disparity among physicians on this topic,” an oncologist respondent wrote.

At one end of the spectrum, 3% of doctors felt that abortions should never be permitted. “The human baby in the womb is an independent person with the right to life,” a pathologist said. At the other end, nearly one-fourth of physicians believed abortion should be accessible under all circumstances, regardless of trimester or reason. “I am just here to support the woman and make her decision a reality,” an internist said.

While saying an abortion should be granted after “fetal viability” only “in extenuating circumstances,” an ob.gyn. respondent said she is “extremely concerned” about attacks on abortion rights. “Some of us are old enough to remember women coming to the ER in extremis after illegal procedures, prior to Roe v. Wade.”

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

CHICAGO – In patients with chronic limb-threatening ischemia (CLTI) and a usable saphenous vein segment, a surgical procedure leads to better outcomes than an endovascular approach, according results of the multinational randomized BEST-CLI trial.

In that study, conducted with two cohorts, the advantage of surgery was limited to the group with an available saphenous vein, but in this group the advantage over an endovascular approach was substantial, according to Alik Farber, MD, chief of vascular and endovascular surgery at Boston University.

Ted Bosworth/MDedge News

“Bypass with adequate saphenous vein should be offered as a first-line treatment option for suitable candidates with CLTI as part of fully informed, shared decision-making,” Dr. Farber stated in presenting the results at the annual scientific sessions of the American Heart Association.

The study pursued two hypotheses, which is why CLTI patients were divided into two cohorts. For cohort 1, which was limited to CLTI patients with an available saphenous vein, it was predicted that surgery would be better than an endovascular approach. For cohort 2, which enrolled patients who needed an alternative conduit, the hypothesis was that endovascular procedures would prove superior.

The study confirmed the first hypothesis, but there was no difference between the two approaches for the composite primary outcome of major adverse limb events (MALE) in the second cohort.
 

Saphenous vein availability determined cohort

Candidates for the BEST-CLI (Best Endovascular versus Best Surgical Therapy in Patients with CLTI) trial had to have CLTI producing severe ischemia and to be judged by both surgeons and cardiovascular specialists to be candidates for both types of interventions. Eligible patients were then enrolled in cohort 1 if the saphenous vein was considered the best conduit on imaging. If not, they were enrolled in cohort 2.

Patients were randomized to undergo surgical or endovascular repair only after the cohort was assigned. The primary composite MALE endpoint consisted of an adjudicated first major reintervention, such as new bypass or thrombectomy, an above-the-ankle amputation, or death from any cause.

In cohort 1, the primary composite MALE endpoint was reached in 42.6% of those in surgical arm and 57.4% in the endovascular arm, translating into a 32% relative risk reduction (hazard ratio, 0.68; P < .001) in favor of surgery at the end of a median of 2.7 years of follow-up.

The main advantage was the difference in reinterventions. The lower rate in the surgical group (9.2% vs. 23.5%), translated into a 65% relative risk reduction for this endpoint (HR, 035; P < .001).

The reduction in above-ankle amputations in the surgical group (10.4% vs. 14.9%) was also significant (HR, 0.73; P = .04), but the reduction in all-cause mortality (33.0% vs. 37.6%) was not (HR, 0.98; P = .81).

BEST-CLI involved 150 sites in North America, Europe, and New Zealand. Cohort 1, which randomized 1,434 patients, was the larger of the two. In the second cohort, only 396 patients were randomized, which Dr. Farber said “might have been underpowered.”

The results were published in the New England Journal of Medicine simultaneously with presentation of the results at the meeting.

After a median follow-up of 1.6 years in cohort 2, the slightly lower proportion of patients who reached the composite MALE endpoint in the surgical group relative to the endovascular group (42.8% vs. 47.7%) did not translate into a significant advantage (HR, 0.79; P = .12).

For the individual components, the lower rate of reinterventions in the surgical arm (14.4% vs. 25.6%) did reach statistical significance (HR, 0.47; P = .002), but both amputation (14.9% vs. 14.1%) and all-cause death (26.3% vs. 24.1%) were numerically but not significantly higher in the surgical group.

The primary safety endpoint was major adverse cardiovascular events (MACE). This was not significantly different in either cohort. There were also no major differences between groups in the risk of perioperative complications.

Level 1 evidence provided for intervention choice

Overall, BEST-CLI showed that both surgical and endovascular revascularizations are effective and safe, according to Dr. Farber. As a result, he suggested that both can be considered even if a saphenous vein is available when specific patient characteristics make one more attractive than another.

Yet, in a general population with an available saphenous vein, these data provide “level 1 evidence” that a surgical approach should be the dominant choice, he added.

Ted Bosworth/MDedge News

A quality of life (QOL) substudy of BEST-CLI did not challenge this conclusion. Rather, the main finding was that restoring circulation by either approach has a major favorable impact on patient well-being, according to Matthew Menard, MD, codirector of endovascular surgery at Brigham and Women’s Hospital, Boston.

In this substudy, presented separately from the primary BEST-CLI results, that analysis confirmed that baseline QOL was extremely poor, whether measured with a disease specific instrument such as VascuQol, or generic instruments, such as SF-12.

Surgical or endovascular treatment produced clinically meaningful and sustained improvements in every QOL measure employed, according to Dr. Menard, and this was true in either cohort.
 

Results not necessarily relevant to all

These data are likely relevant to the patients evaluated, but “it is important to consider who made it into this trial,” according to Naomi M. Hamburg, MD, section chief of vascular biology at Boston University.

Ted Bosworth/MDedge News

Not least, patients had to be candidates for either surgical or endovascular repair to get into the study, omitting those patients not deemed by the investigators to be suited for either.

In addition, Dr. Hamburg pointed out that there was a low enrollment of Blacks (20%) and women (28%), two groups for whom CTLI is a common condition.

Lastly, Dr Hamburg questioned whether specific types of anatomy might be better suited to one procedure relative to another, a variable not considered in this study. Reassured by Dr. Farber that this will be explored in subsequent analyses of BEST-CLI data, Dr. Hamburg expressed interest in learning the results.

Dr. Hamburg was among those who spoke about the growing urgency to optimize strategies for early diagnosis and treatment of CTLI. She plugged the PAD National Action Plan as one of the efforts to thwart the coming wave of CTLI expected from the steep climb in the prevalence of diabetes in the United States.

Dr. Farber reported a financial relationship with Sanifit Therapeutics. The study was funded by the National Heart, Lung, and Blood Institute, but received additional support from multiple pharmaceutical companies. Dr. Menard reported a financial relationship with Janssen Pharmaceuticals. Dr. Hamburg reported financial relationships with Acceleron Pharma, Merck, NovoNordisk, and Sanifit.

CHICAGO – In patients with chronic limb-threatening ischemia (CLTI) and a usable saphenous vein segment, a surgical procedure leads to better outcomes than an endovascular approach, according results of the multinational randomized BEST-CLI trial.

In that study, conducted with two cohorts, the advantage of surgery was limited to the group with an available saphenous vein, but in this group the advantage over an endovascular approach was substantial, according to Alik Farber, MD, chief of vascular and endovascular surgery at Boston University.

Ted Bosworth/MDedge News

“Bypass with adequate saphenous vein should be offered as a first-line treatment option for suitable candidates with CLTI as part of fully informed, shared decision-making,” Dr. Farber stated in presenting the results at the annual scientific sessions of the American Heart Association.

The study pursued two hypotheses, which is why CLTI patients were divided into two cohorts. For cohort 1, which was limited to CLTI patients with an available saphenous vein, it was predicted that surgery would be better than an endovascular approach. For cohort 2, which enrolled patients who needed an alternative conduit, the hypothesis was that endovascular procedures would prove superior.

The study confirmed the first hypothesis, but there was no difference between the two approaches for the composite primary outcome of major adverse limb events (MALE) in the second cohort.
 

Saphenous vein availability determined cohort

Candidates for the BEST-CLI (Best Endovascular versus Best Surgical Therapy in Patients with CLTI) trial had to have CLTI producing severe ischemia and to be judged by both surgeons and cardiovascular specialists to be candidates for both types of interventions. Eligible patients were then enrolled in cohort 1 if the saphenous vein was considered the best conduit on imaging. If not, they were enrolled in cohort 2.

Patients were randomized to undergo surgical or endovascular repair only after the cohort was assigned. The primary composite MALE endpoint consisted of an adjudicated first major reintervention, such as new bypass or thrombectomy, an above-the-ankle amputation, or death from any cause.

In cohort 1, the primary composite MALE endpoint was reached in 42.6% of those in surgical arm and 57.4% in the endovascular arm, translating into a 32% relative risk reduction (hazard ratio, 0.68; P < .001) in favor of surgery at the end of a median of 2.7 years of follow-up.

The main advantage was the difference in reinterventions. The lower rate in the surgical group (9.2% vs. 23.5%), translated into a 65% relative risk reduction for this endpoint (HR, 035; P < .001).

The reduction in above-ankle amputations in the surgical group (10.4% vs. 14.9%) was also significant (HR, 0.73; P = .04), but the reduction in all-cause mortality (33.0% vs. 37.6%) was not (HR, 0.98; P = .81).

BEST-CLI involved 150 sites in North America, Europe, and New Zealand. Cohort 1, which randomized 1,434 patients, was the larger of the two. In the second cohort, only 396 patients were randomized, which Dr. Farber said “might have been underpowered.”

The results were published in the New England Journal of Medicine simultaneously with presentation of the results at the meeting.

After a median follow-up of 1.6 years in cohort 2, the slightly lower proportion of patients who reached the composite MALE endpoint in the surgical group relative to the endovascular group (42.8% vs. 47.7%) did not translate into a significant advantage (HR, 0.79; P = .12).

For the individual components, the lower rate of reinterventions in the surgical arm (14.4% vs. 25.6%) did reach statistical significance (HR, 0.47; P = .002), but both amputation (14.9% vs. 14.1%) and all-cause death (26.3% vs. 24.1%) were numerically but not significantly higher in the surgical group.

The primary safety endpoint was major adverse cardiovascular events (MACE). This was not significantly different in either cohort. There were also no major differences between groups in the risk of perioperative complications.

Level 1 evidence provided for intervention choice

Overall, BEST-CLI showed that both surgical and endovascular revascularizations are effective and safe, according to Dr. Farber. As a result, he suggested that both can be considered even if a saphenous vein is available when specific patient characteristics make one more attractive than another.

Yet, in a general population with an available saphenous vein, these data provide “level 1 evidence” that a surgical approach should be the dominant choice, he added.

Ted Bosworth/MDedge News

A quality of life (QOL) substudy of BEST-CLI did not challenge this conclusion. Rather, the main finding was that restoring circulation by either approach has a major favorable impact on patient well-being, according to Matthew Menard, MD, codirector of endovascular surgery at Brigham and Women’s Hospital, Boston.

In this substudy, presented separately from the primary BEST-CLI results, that analysis confirmed that baseline QOL was extremely poor, whether measured with a disease specific instrument such as VascuQol, or generic instruments, such as SF-12.

Surgical or endovascular treatment produced clinically meaningful and sustained improvements in every QOL measure employed, according to Dr. Menard, and this was true in either cohort.
 

Results not necessarily relevant to all

These data are likely relevant to the patients evaluated, but “it is important to consider who made it into this trial,” according to Naomi M. Hamburg, MD, section chief of vascular biology at Boston University.

Ted Bosworth/MDedge News

Not least, patients had to be candidates for either surgical or endovascular repair to get into the study, omitting those patients not deemed by the investigators to be suited for either.

In addition, Dr. Hamburg pointed out that there was a low enrollment of Blacks (20%) and women (28%), two groups for whom CTLI is a common condition.

Lastly, Dr Hamburg questioned whether specific types of anatomy might be better suited to one procedure relative to another, a variable not considered in this study. Reassured by Dr. Farber that this will be explored in subsequent analyses of BEST-CLI data, Dr. Hamburg expressed interest in learning the results.

Dr. Hamburg was among those who spoke about the growing urgency to optimize strategies for early diagnosis and treatment of CTLI. She plugged the PAD National Action Plan as one of the efforts to thwart the coming wave of CTLI expected from the steep climb in the prevalence of diabetes in the United States.

Dr. Farber reported a financial relationship with Sanifit Therapeutics. The study was funded by the National Heart, Lung, and Blood Institute, but received additional support from multiple pharmaceutical companies. Dr. Menard reported a financial relationship with Janssen Pharmaceuticals. Dr. Hamburg reported financial relationships with Acceleron Pharma, Merck, NovoNordisk, and Sanifit.

CHICAGO – In patients with chronic limb-threatening ischemia (CLTI) and a usable saphenous vein segment, a surgical procedure leads to better outcomes than an endovascular approach, according results of the multinational randomized BEST-CLI trial.

In that study, conducted with two cohorts, the advantage of surgery was limited to the group with an available saphenous vein, but in this group the advantage over an endovascular approach was substantial, according to Alik Farber, MD, chief of vascular and endovascular surgery at Boston University.

Ted Bosworth/MDedge News

“Bypass with adequate saphenous vein should be offered as a first-line treatment option for suitable candidates with CLTI as part of fully informed, shared decision-making,” Dr. Farber stated in presenting the results at the annual scientific sessions of the American Heart Association.

The study pursued two hypotheses, which is why CLTI patients were divided into two cohorts. For cohort 1, which was limited to CLTI patients with an available saphenous vein, it was predicted that surgery would be better than an endovascular approach. For cohort 2, which enrolled patients who needed an alternative conduit, the hypothesis was that endovascular procedures would prove superior.

The study confirmed the first hypothesis, but there was no difference between the two approaches for the composite primary outcome of major adverse limb events (MALE) in the second cohort.
 

Saphenous vein availability determined cohort

Candidates for the BEST-CLI (Best Endovascular versus Best Surgical Therapy in Patients with CLTI) trial had to have CLTI producing severe ischemia and to be judged by both surgeons and cardiovascular specialists to be candidates for both types of interventions. Eligible patients were then enrolled in cohort 1 if the saphenous vein was considered the best conduit on imaging. If not, they were enrolled in cohort 2.

Patients were randomized to undergo surgical or endovascular repair only after the cohort was assigned. The primary composite MALE endpoint consisted of an adjudicated first major reintervention, such as new bypass or thrombectomy, an above-the-ankle amputation, or death from any cause.

In cohort 1, the primary composite MALE endpoint was reached in 42.6% of those in surgical arm and 57.4% in the endovascular arm, translating into a 32% relative risk reduction (hazard ratio, 0.68; P < .001) in favor of surgery at the end of a median of 2.7 years of follow-up.

The main advantage was the difference in reinterventions. The lower rate in the surgical group (9.2% vs. 23.5%), translated into a 65% relative risk reduction for this endpoint (HR, 035; P < .001).

The reduction in above-ankle amputations in the surgical group (10.4% vs. 14.9%) was also significant (HR, 0.73; P = .04), but the reduction in all-cause mortality (33.0% vs. 37.6%) was not (HR, 0.98; P = .81).

BEST-CLI involved 150 sites in North America, Europe, and New Zealand. Cohort 1, which randomized 1,434 patients, was the larger of the two. In the second cohort, only 396 patients were randomized, which Dr. Farber said “might have been underpowered.”

The results were published in the New England Journal of Medicine simultaneously with presentation of the results at the meeting.

After a median follow-up of 1.6 years in cohort 2, the slightly lower proportion of patients who reached the composite MALE endpoint in the surgical group relative to the endovascular group (42.8% vs. 47.7%) did not translate into a significant advantage (HR, 0.79; P = .12).

For the individual components, the lower rate of reinterventions in the surgical arm (14.4% vs. 25.6%) did reach statistical significance (HR, 0.47; P = .002), but both amputation (14.9% vs. 14.1%) and all-cause death (26.3% vs. 24.1%) were numerically but not significantly higher in the surgical group.

The primary safety endpoint was major adverse cardiovascular events (MACE). This was not significantly different in either cohort. There were also no major differences between groups in the risk of perioperative complications.

Level 1 evidence provided for intervention choice

Overall, BEST-CLI showed that both surgical and endovascular revascularizations are effective and safe, according to Dr. Farber. As a result, he suggested that both can be considered even if a saphenous vein is available when specific patient characteristics make one more attractive than another.

Yet, in a general population with an available saphenous vein, these data provide “level 1 evidence” that a surgical approach should be the dominant choice, he added.

Ted Bosworth/MDedge News

A quality of life (QOL) substudy of BEST-CLI did not challenge this conclusion. Rather, the main finding was that restoring circulation by either approach has a major favorable impact on patient well-being, according to Matthew Menard, MD, codirector of endovascular surgery at Brigham and Women’s Hospital, Boston.

In this substudy, presented separately from the primary BEST-CLI results, that analysis confirmed that baseline QOL was extremely poor, whether measured with a disease specific instrument such as VascuQol, or generic instruments, such as SF-12.

Surgical or endovascular treatment produced clinically meaningful and sustained improvements in every QOL measure employed, according to Dr. Menard, and this was true in either cohort.
 

Results not necessarily relevant to all

These data are likely relevant to the patients evaluated, but “it is important to consider who made it into this trial,” according to Naomi M. Hamburg, MD, section chief of vascular biology at Boston University.

Ted Bosworth/MDedge News

Not least, patients had to be candidates for either surgical or endovascular repair to get into the study, omitting those patients not deemed by the investigators to be suited for either.

In addition, Dr. Hamburg pointed out that there was a low enrollment of Blacks (20%) and women (28%), two groups for whom CTLI is a common condition.

Lastly, Dr Hamburg questioned whether specific types of anatomy might be better suited to one procedure relative to another, a variable not considered in this study. Reassured by Dr. Farber that this will be explored in subsequent analyses of BEST-CLI data, Dr. Hamburg expressed interest in learning the results.

Dr. Hamburg was among those who spoke about the growing urgency to optimize strategies for early diagnosis and treatment of CTLI. She plugged the PAD National Action Plan as one of the efforts to thwart the coming wave of CTLI expected from the steep climb in the prevalence of diabetes in the United States.

Dr. Farber reported a financial relationship with Sanifit Therapeutics. The study was funded by the National Heart, Lung, and Blood Institute, but received additional support from multiple pharmaceutical companies. Dr. Menard reported a financial relationship with Janssen Pharmaceuticals. Dr. Hamburg reported financial relationships with Acceleron Pharma, Merck, NovoNordisk, and Sanifit.

CHICAGO – A clinical decision-support tool designed to identify hospitalized patients who need thromboembolism prophylaxis and embedded in a hospital’s electronic health record led to significantly more appropriate prophylaxis, compared with usual care, and significantly cut the 30-day rate of thromboembolism in a randomized, multicenter trial with more than 10,000 patients.

“This is the first time that a clinical decision support tool not only changed [thromboprophylaxis prescribing] behavior but also affected hard outcomes. That’s remarkable,” lead investigator Alex C. Spyropoulos, MD, said in an interview.

Even so, outside experts expressed concerns about certain results and the trial design.

Mitchel L. Zoler/MDedge News

Use of the decision-support risk calculator for thromboembolism in the IMPROVE-DD VTE trial significantly boosted use of appropriate inpatient thromboprophylaxis starting at hospital admission by a relative 52%, and significantly increased outpatient thromboprophylaxis prescribed at discharge by a relative 93% in the study’s two primary endpoints, Dr. Spyropoulos reported at the American Heart Association scientific sessions.

This intervention led to a significant 29% relative reduction in the incidence of total thromboembolic events, both venous and arterial, during hospitalization and through 30 days post discharge.

The absolute thromboembolic event rates were 2.9% among 5,249 patients treated at either of two U.S. hospitals that used the EHR-based risk calculator and 4.0% in 5,450 patients seen at either of two other U.S. hospitals that served as controls and where usual care method identified patients who needed thromboprophylaxis, said Dr. Spyropoulos, professor and director of the anticoagulation and clinical thrombosis services for Northwell Health in New York. This included a 2.7% rate of venous thromboembolism and a 0.25% rate of arterial thromboembolism in the intervention patients, and a 3.3% rate of venous events and a 0.7% rate of arterial events in the controls.

Patients treated at the hospitals that used the EHR-embedded risk calculator also has a numerically lower rate of major bleeding events during hospitalization and 30-day postdischarge follow-up, a 0.15% rate compared with a 0.22% rate in the control patients, a difference that was not significant.
 

A ‘powerful message’

“It’s a powerful message to see an absolute 1.1% difference in the rate of thromboembolism and a trend to fewer major bleeds. I think this will change practice,” Dr. Spyropoulos added in the interview. “The next step is dissemination.”

But thromboprophylaxis experts cautioned that, while the results looked promising, the findings need more analysis and review, and the intervention may need further testing before it’s ready for widespread use.

For example, one unexpected result was an unexpected 2.1 percentage point increase in all-cause mortality linked with use of the decision-support tool. Total deaths from admission to 30 days after discharge occurred in 9.1% of the patients treated at the two hospitals that used the risk calculator and 7.0% among the control patients, a difference that Dr, Spyropoulos said was likely the result of unbalanced outcomes from COVID-19 infections that had no relevance to the tested intervention. The trial ran during December 2020–January 2022.
 

But wait – more detail and analysis needed

“I’d like to see more analysis of the data from this trial,” and “there is the issue of increased mortality,” commented Gregory Piazza, MD, director of vascular medicine at Brigham and Women’s Hospital in Boston, and a specialist in thromboembolism prevention and management. He also highlighted the need for greater detail on the arterial thromboembolic events tallied during the study.

With more details and analysis of these findings “we’ll learn more about the true impact” of this intervention, Dr. Piazza said in an interview.

Mitchel L. Zoler/MDedge News

“The increased mortality in the intervention group may have been due to differential treatment and decision-making and confounding and warrants further investigation,” commented Elaine M. Hylek, MD, a professor at Boston University and designated discussant for the report. Selection bias may have contributed to this possible confounding, Dr. Hylek noted.

Other limitations of the study cited by Dr. Hylek included its reliance on individual clinician decision-making to actually prescribe thromboprophylaxis, a lack of information on patient adherence to their thromboprophylaxis prescription, and an overall low rate of appropriate thromboprophylaxis prescribed to patients at discharge. The rates were 7.5% among the controls and 13.6% among patients in the intervention arm. For prescription at the time of hospitalization, the rates were 72.5% among control patients and 80.1% for patients seen at the two hospitals that used the decision-support tool.
 

The IMPROVE-DD VTE risk assessment tool

The clinical decision-support tool tested is called the IMPROVE-DD VTE risk assessment model, developed over several years by Dr. Spyropoulos and associates; they have also performed multiple validation studies. The model includes eight factors that score 1-3 points if positive that can add up to total scores of 0-14. A score of 0 or 1 is considered low risk, 2 or 3 intermediate risk, and 4 or more high risk. One of the scoring factors is the result of a D-dimer test, which explains the DD part of the name.

The eight factors and point assignments are prior venous thromboembolism: 3 points; known thrombophilia: 2 points; lower limb paralysis: 2 points; current cancer: 2 points; d-dimer level more than twofold the upper limit of normal: 2 points; immobilized for at least 7 days: 1 point; admitted to the ICU or coronary care unit: 1 point; and age greater than 60 years old: 1 point.

Development of the IMPROVE-DD VTE risk calculator received most of its funding from the U.S. Agency for Healthcare Research and Quality, and the risk tool will be available for hospitals and health systems to access at no charge through the agency’s website, Dr. Spyropoulos said. The researchers designed the calculator to operate in any EHR product.

IMPROVE-DD VTE “is a very valid, high-quality tool,” commented Dr. Piazza. “We’ve used some rather blunt tools in the past,” and especially praised inclusion of D-dimer results into the IMPROVE-DD VTE model.

“It’s nice to use a biomarker in addition to clinical factors,” he said. “A biomarker provides a more holistic picture; we can’t do genetic testing on every patient.”

Enrollment focused on higher-risk patients

The study ran at four academic, tertiary-care hospitals in the Northwell Health network in the New York region. It enrolled patients aged more than 60 years who were hospitalized for any of five diagnoses: heart failure; acute respiratory insufficiency, including chronic obstructive lung disease or asthma; acute infectious disease, including COVID-19; acute inflammatory disease, including rheumatic disease; or acute stroke. The study excluded patients with a history of atrial fibrillation, those who used an anticoagulant at home, or those who had received therapeutic anticoagulation within 24 hours of their hospital admission.

The anticoagulant prophylaxis that patients received depended on their calculated risk level – intermediate or high – and whether they were inpatients or being discharged. The anticoagulants that clinicians could prescribe included unfractionated heparin, enoxaparin, fondaparinux, rivaroxaban, and apixaban.

“We’ve been looking for a long time for a tool for medically ill patients that’s like the CHA2DS2-VASc score” for patients with atrial fibrillation. “These powerful data say we now have this, and the EHR provides a vehicle to easily implement it,” Dr. Spyropoulos said.

The IMPROVE-DD VTE study received partial funding from Janssen. Dr. Spyropoulos has been a consultant to Nayer, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Pfizer, and Sanofi; adviser to the ATLAS Group; and has received research support from Janssen. Dr. Piazza has received research funding from Bayer, BIG/EKOS, BMS, Janssen, and Portola. Dr. Hylek had been a consultant to Bayer and Ionis, and has received honoraria from Boehringer Ingelheim and Pfizer.

CHICAGO – A clinical decision-support tool designed to identify hospitalized patients who need thromboembolism prophylaxis and embedded in a hospital’s electronic health record led to significantly more appropriate prophylaxis, compared with usual care, and significantly cut the 30-day rate of thromboembolism in a randomized, multicenter trial with more than 10,000 patients.

“This is the first time that a clinical decision support tool not only changed [thromboprophylaxis prescribing] behavior but also affected hard outcomes. That’s remarkable,” lead investigator Alex C. Spyropoulos, MD, said in an interview.

Even so, outside experts expressed concerns about certain results and the trial design.

Mitchel L. Zoler/MDedge News

Use of the decision-support risk calculator for thromboembolism in the IMPROVE-DD VTE trial significantly boosted use of appropriate inpatient thromboprophylaxis starting at hospital admission by a relative 52%, and significantly increased outpatient thromboprophylaxis prescribed at discharge by a relative 93% in the study’s two primary endpoints, Dr. Spyropoulos reported at the American Heart Association scientific sessions.

This intervention led to a significant 29% relative reduction in the incidence of total thromboembolic events, both venous and arterial, during hospitalization and through 30 days post discharge.

The absolute thromboembolic event rates were 2.9% among 5,249 patients treated at either of two U.S. hospitals that used the EHR-based risk calculator and 4.0% in 5,450 patients seen at either of two other U.S. hospitals that served as controls and where usual care method identified patients who needed thromboprophylaxis, said Dr. Spyropoulos, professor and director of the anticoagulation and clinical thrombosis services for Northwell Health in New York. This included a 2.7% rate of venous thromboembolism and a 0.25% rate of arterial thromboembolism in the intervention patients, and a 3.3% rate of venous events and a 0.7% rate of arterial events in the controls.

Patients treated at the hospitals that used the EHR-embedded risk calculator also has a numerically lower rate of major bleeding events during hospitalization and 30-day postdischarge follow-up, a 0.15% rate compared with a 0.22% rate in the control patients, a difference that was not significant.
 

A ‘powerful message’

“It’s a powerful message to see an absolute 1.1% difference in the rate of thromboembolism and a trend to fewer major bleeds. I think this will change practice,” Dr. Spyropoulos added in the interview. “The next step is dissemination.”

But thromboprophylaxis experts cautioned that, while the results looked promising, the findings need more analysis and review, and the intervention may need further testing before it’s ready for widespread use.

For example, one unexpected result was an unexpected 2.1 percentage point increase in all-cause mortality linked with use of the decision-support tool. Total deaths from admission to 30 days after discharge occurred in 9.1% of the patients treated at the two hospitals that used the risk calculator and 7.0% among the control patients, a difference that Dr, Spyropoulos said was likely the result of unbalanced outcomes from COVID-19 infections that had no relevance to the tested intervention. The trial ran during December 2020–January 2022.
 

But wait – more detail and analysis needed

“I’d like to see more analysis of the data from this trial,” and “there is the issue of increased mortality,” commented Gregory Piazza, MD, director of vascular medicine at Brigham and Women’s Hospital in Boston, and a specialist in thromboembolism prevention and management. He also highlighted the need for greater detail on the arterial thromboembolic events tallied during the study.

With more details and analysis of these findings “we’ll learn more about the true impact” of this intervention, Dr. Piazza said in an interview.

Mitchel L. Zoler/MDedge News

“The increased mortality in the intervention group may have been due to differential treatment and decision-making and confounding and warrants further investigation,” commented Elaine M. Hylek, MD, a professor at Boston University and designated discussant for the report. Selection bias may have contributed to this possible confounding, Dr. Hylek noted.

Other limitations of the study cited by Dr. Hylek included its reliance on individual clinician decision-making to actually prescribe thromboprophylaxis, a lack of information on patient adherence to their thromboprophylaxis prescription, and an overall low rate of appropriate thromboprophylaxis prescribed to patients at discharge. The rates were 7.5% among the controls and 13.6% among patients in the intervention arm. For prescription at the time of hospitalization, the rates were 72.5% among control patients and 80.1% for patients seen at the two hospitals that used the decision-support tool.
 

The IMPROVE-DD VTE risk assessment tool

The clinical decision-support tool tested is called the IMPROVE-DD VTE risk assessment model, developed over several years by Dr. Spyropoulos and associates; they have also performed multiple validation studies. The model includes eight factors that score 1-3 points if positive that can add up to total scores of 0-14. A score of 0 or 1 is considered low risk, 2 or 3 intermediate risk, and 4 or more high risk. One of the scoring factors is the result of a D-dimer test, which explains the DD part of the name.

The eight factors and point assignments are prior venous thromboembolism: 3 points; known thrombophilia: 2 points; lower limb paralysis: 2 points; current cancer: 2 points; d-dimer level more than twofold the upper limit of normal: 2 points; immobilized for at least 7 days: 1 point; admitted to the ICU or coronary care unit: 1 point; and age greater than 60 years old: 1 point.

Development of the IMPROVE-DD VTE risk calculator received most of its funding from the U.S. Agency for Healthcare Research and Quality, and the risk tool will be available for hospitals and health systems to access at no charge through the agency’s website, Dr. Spyropoulos said. The researchers designed the calculator to operate in any EHR product.

IMPROVE-DD VTE “is a very valid, high-quality tool,” commented Dr. Piazza. “We’ve used some rather blunt tools in the past,” and especially praised inclusion of D-dimer results into the IMPROVE-DD VTE model.

“It’s nice to use a biomarker in addition to clinical factors,” he said. “A biomarker provides a more holistic picture; we can’t do genetic testing on every patient.”

Enrollment focused on higher-risk patients

The study ran at four academic, tertiary-care hospitals in the Northwell Health network in the New York region. It enrolled patients aged more than 60 years who were hospitalized for any of five diagnoses: heart failure; acute respiratory insufficiency, including chronic obstructive lung disease or asthma; acute infectious disease, including COVID-19; acute inflammatory disease, including rheumatic disease; or acute stroke. The study excluded patients with a history of atrial fibrillation, those who used an anticoagulant at home, or those who had received therapeutic anticoagulation within 24 hours of their hospital admission.

The anticoagulant prophylaxis that patients received depended on their calculated risk level – intermediate or high – and whether they were inpatients or being discharged. The anticoagulants that clinicians could prescribe included unfractionated heparin, enoxaparin, fondaparinux, rivaroxaban, and apixaban.

“We’ve been looking for a long time for a tool for medically ill patients that’s like the CHA2DS2-VASc score” for patients with atrial fibrillation. “These powerful data say we now have this, and the EHR provides a vehicle to easily implement it,” Dr. Spyropoulos said.

The IMPROVE-DD VTE study received partial funding from Janssen. Dr. Spyropoulos has been a consultant to Nayer, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Pfizer, and Sanofi; adviser to the ATLAS Group; and has received research support from Janssen. Dr. Piazza has received research funding from Bayer, BIG/EKOS, BMS, Janssen, and Portola. Dr. Hylek had been a consultant to Bayer and Ionis, and has received honoraria from Boehringer Ingelheim and Pfizer.

CHICAGO – A clinical decision-support tool designed to identify hospitalized patients who need thromboembolism prophylaxis and embedded in a hospital’s electronic health record led to significantly more appropriate prophylaxis, compared with usual care, and significantly cut the 30-day rate of thromboembolism in a randomized, multicenter trial with more than 10,000 patients.

“This is the first time that a clinical decision support tool not only changed [thromboprophylaxis prescribing] behavior but also affected hard outcomes. That’s remarkable,” lead investigator Alex C. Spyropoulos, MD, said in an interview.

Even so, outside experts expressed concerns about certain results and the trial design.

Mitchel L. Zoler/MDedge News

Use of the decision-support risk calculator for thromboembolism in the IMPROVE-DD VTE trial significantly boosted use of appropriate inpatient thromboprophylaxis starting at hospital admission by a relative 52%, and significantly increased outpatient thromboprophylaxis prescribed at discharge by a relative 93% in the study’s two primary endpoints, Dr. Spyropoulos reported at the American Heart Association scientific sessions.

This intervention led to a significant 29% relative reduction in the incidence of total thromboembolic events, both venous and arterial, during hospitalization and through 30 days post discharge.

The absolute thromboembolic event rates were 2.9% among 5,249 patients treated at either of two U.S. hospitals that used the EHR-based risk calculator and 4.0% in 5,450 patients seen at either of two other U.S. hospitals that served as controls and where usual care method identified patients who needed thromboprophylaxis, said Dr. Spyropoulos, professor and director of the anticoagulation and clinical thrombosis services for Northwell Health in New York. This included a 2.7% rate of venous thromboembolism and a 0.25% rate of arterial thromboembolism in the intervention patients, and a 3.3% rate of venous events and a 0.7% rate of arterial events in the controls.

Patients treated at the hospitals that used the EHR-embedded risk calculator also has a numerically lower rate of major bleeding events during hospitalization and 30-day postdischarge follow-up, a 0.15% rate compared with a 0.22% rate in the control patients, a difference that was not significant.
 

A ‘powerful message’

“It’s a powerful message to see an absolute 1.1% difference in the rate of thromboembolism and a trend to fewer major bleeds. I think this will change practice,” Dr. Spyropoulos added in the interview. “The next step is dissemination.”

But thromboprophylaxis experts cautioned that, while the results looked promising, the findings need more analysis and review, and the intervention may need further testing before it’s ready for widespread use.

For example, one unexpected result was an unexpected 2.1 percentage point increase in all-cause mortality linked with use of the decision-support tool. Total deaths from admission to 30 days after discharge occurred in 9.1% of the patients treated at the two hospitals that used the risk calculator and 7.0% among the control patients, a difference that Dr, Spyropoulos said was likely the result of unbalanced outcomes from COVID-19 infections that had no relevance to the tested intervention. The trial ran during December 2020–January 2022.
 

But wait – more detail and analysis needed

“I’d like to see more analysis of the data from this trial,” and “there is the issue of increased mortality,” commented Gregory Piazza, MD, director of vascular medicine at Brigham and Women’s Hospital in Boston, and a specialist in thromboembolism prevention and management. He also highlighted the need for greater detail on the arterial thromboembolic events tallied during the study.

With more details and analysis of these findings “we’ll learn more about the true impact” of this intervention, Dr. Piazza said in an interview.

Mitchel L. Zoler/MDedge News

“The increased mortality in the intervention group may have been due to differential treatment and decision-making and confounding and warrants further investigation,” commented Elaine M. Hylek, MD, a professor at Boston University and designated discussant for the report. Selection bias may have contributed to this possible confounding, Dr. Hylek noted.

Other limitations of the study cited by Dr. Hylek included its reliance on individual clinician decision-making to actually prescribe thromboprophylaxis, a lack of information on patient adherence to their thromboprophylaxis prescription, and an overall low rate of appropriate thromboprophylaxis prescribed to patients at discharge. The rates were 7.5% among the controls and 13.6% among patients in the intervention arm. For prescription at the time of hospitalization, the rates were 72.5% among control patients and 80.1% for patients seen at the two hospitals that used the decision-support tool.
 

The IMPROVE-DD VTE risk assessment tool

The clinical decision-support tool tested is called the IMPROVE-DD VTE risk assessment model, developed over several years by Dr. Spyropoulos and associates; they have also performed multiple validation studies. The model includes eight factors that score 1-3 points if positive that can add up to total scores of 0-14. A score of 0 or 1 is considered low risk, 2 or 3 intermediate risk, and 4 or more high risk. One of the scoring factors is the result of a D-dimer test, which explains the DD part of the name.

The eight factors and point assignments are prior venous thromboembolism: 3 points; known thrombophilia: 2 points; lower limb paralysis: 2 points; current cancer: 2 points; d-dimer level more than twofold the upper limit of normal: 2 points; immobilized for at least 7 days: 1 point; admitted to the ICU or coronary care unit: 1 point; and age greater than 60 years old: 1 point.

Development of the IMPROVE-DD VTE risk calculator received most of its funding from the U.S. Agency for Healthcare Research and Quality, and the risk tool will be available for hospitals and health systems to access at no charge through the agency’s website, Dr. Spyropoulos said. The researchers designed the calculator to operate in any EHR product.

IMPROVE-DD VTE “is a very valid, high-quality tool,” commented Dr. Piazza. “We’ve used some rather blunt tools in the past,” and especially praised inclusion of D-dimer results into the IMPROVE-DD VTE model.

“It’s nice to use a biomarker in addition to clinical factors,” he said. “A biomarker provides a more holistic picture; we can’t do genetic testing on every patient.”

Enrollment focused on higher-risk patients

The study ran at four academic, tertiary-care hospitals in the Northwell Health network in the New York region. It enrolled patients aged more than 60 years who were hospitalized for any of five diagnoses: heart failure; acute respiratory insufficiency, including chronic obstructive lung disease or asthma; acute infectious disease, including COVID-19; acute inflammatory disease, including rheumatic disease; or acute stroke. The study excluded patients with a history of atrial fibrillation, those who used an anticoagulant at home, or those who had received therapeutic anticoagulation within 24 hours of their hospital admission.

The anticoagulant prophylaxis that patients received depended on their calculated risk level – intermediate or high – and whether they were inpatients or being discharged. The anticoagulants that clinicians could prescribe included unfractionated heparin, enoxaparin, fondaparinux, rivaroxaban, and apixaban.

“We’ve been looking for a long time for a tool for medically ill patients that’s like the CHA2DS2-VASc score” for patients with atrial fibrillation. “These powerful data say we now have this, and the EHR provides a vehicle to easily implement it,” Dr. Spyropoulos said.

The IMPROVE-DD VTE study received partial funding from Janssen. Dr. Spyropoulos has been a consultant to Nayer, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Pfizer, and Sanofi; adviser to the ATLAS Group; and has received research support from Janssen. Dr. Piazza has received research funding from Bayer, BIG/EKOS, BMS, Janssen, and Portola. Dr. Hylek had been a consultant to Bayer and Ionis, and has received honoraria from Boehringer Ingelheim and Pfizer.

CHICAGO – None of six commercial dietary supplements widely promoted and taken for lowering LDL cholesterol did the job any better than placebo in a randomized trial of adults without cardiovascular disease but at increased cardiovascular risk.

In contrast, those who took the low dose of a high-potency statin in the eight-arm comparative study showed a significant 38% drop in LDL cholesterol levels over 28 days, a performance that blew away the six supplements containing fish oil, cinnamon, garlic, turmeric, plant sterols, or red yeast rice.

The supplements showed little or no effect on any measured lipid biomarkers, which also included total cholesterol and triglycerides, or C-reactive protein (CRP), which reflects systemic inflammation.

The findings undercut the widespread heart-health marketing claims for such supplements and could potentially restore faith in statins for the many patients looking for alternatives, researchers say.

“We all see patients that have their medication lists littered with dietary supplements,” observed Luke J. Laffin, MD, of the Cleveland Clinic Foundation. And it’s more than just heart patients who use them.

Almost $50 billion is spent on dietary supplements annually in the United States, and recent data suggest that more than three-fourths of the population use them, 18% of those based on specious heart-health claims, Dr. Laffin said in a Nov. 6 presentation at the American Heart Association scientific sessions.

The findings of the Supplements, Placebo, or Rosuvastatin Study (SPORT) and how they are framed for the public “are important for public health,” he said.

“As cardiologists, primary care doctors, and others, we really should use these results to have evidence-based discussions with patients” regarding the value of even low-dose statins and the supplements’ “lack of benefit,” said Dr. Laffin, lead author on the SPORT publication, which was published the same day in the Journal of the American College of Cardiology.

Patients assigned to low-dose rosuvastatin showed a mean 24.4% drop in total cholesterol levels over 28 days, the study’s primary endpoint. That differed from the placebo group and those for each supplement at P < .001.

They also averaged a 19.2% decrease in serum triglycerides, P < .05 for all group comparisons. None of the six supplements was significantly different from placebo for change in levels of either total cholesterol or triglycerides.

Nor were there significant differences in adverse events across the groups; there were no adverse changes in liver or kidney function tests or glucose levels; and there were no signs of musculoskeletal symptoms, the published report notes.
 

How to message the results

The SPORT trial is valuable for “addressing the void of data on supplements and cardiovascular health,” Chiadi E. Ndumele, MD, PhD, Johns Hopkins University, Baltimore, said as the invited discussant following Dr. Laffin’s presentation.

But they also send a reassuring message about statins, he noted. In a recent study of statin-nonadherent patients, 80% “were worried about statin side effects as the primary reason for not taking their statin, and 72% preferred using natural supplements instead of taking their prescription therapy,” Dr. Ndumele said. “The reason for this is clearly mistrust, misinformation, and a lack of evidence.”

The next step, he proposed, should be to get the study’s positive message about statins to the public, and especially patients “who are hesitant about statin use.” The current study “underscores the fact that using a low dose of a high-potency statin is associated with a very, very low risk of side effects.”

At a media briefing on SPORT, Amit Khera, MD, agreed the randomized trial provides some needed evidence that can be discussed with patients. “If someone’s coming to see me for cholesterol, we can say definitively now, at least there is data that these [supplements] don’t help your cholesterol and statins do.” Dr. Khera directs the preventive cardiology program at University of Texas Southwestern Medical Center, Dallas.

“I think for those who are there very specifically to lower their cholesterol, hopefully this will resonate,” he said.

“I personally didn’t see a lot of harms in using these supplements. But I also didn’t see any benefits,” Dr. Khera told this news organization.

“Now, if you’re taking them for other reasons, so be it. But if you need to lower your cholesterol for cardiovascular health reasons,” he said, “you need to know that they are minimally to not effective at all.”

But such supplements still “are not without harm,” Dr. Laffin proposed at the press conference. For example, they have potential for drug-drug interactions, “not only with cardiovascular medicines, but those taken for other reasons,” he said. “There are 90,000 supplements on the market in the United States today, and there are all kinds of potential safety issues associated with them.”

In patient discussions, Dr. Laffin said, “I do not think it’s good enough to say, you can waste your money [on supplements] as long as you’re taking your statin. These can actually be harmful in certain situations.”

SPORT, described as a single-center study, randomly assigned 199 participants from “throughout the Cleveland Clinic Health System in northeast Ohio” to one of the eight treatment groups. The investigators were blinded to treatment assignments, Dr. Laffin reported.
 

High adherence

Entry criteria included age 40 to 75 years with no history of cardiovascular disease, LDL-cholesterol from 70 to 189 mg/dL, and a 5%-20% 10-year risk of atherosclerotic cardiovascular disease by the pooled cohort equations. The predominantly White cohort averaged 64.4 years in age and 59% were women.

They were assigned to receive rosuvastatin 5 mg daily, placebo, or daily doses of supplements, with 25 patients per group, except the fish-oil group, which comprised 24 patients.

The daily supplement dosages were 2,400 mg for fish oil (Nature Made); 2,400 mg for cinnamon (NutriFlair), 5,000 mcg allicin for the garlic (Garlique), 4,500 mg for turmeric curcumin (BioSchwartz), 1,600 mg plant sterols (CholestOff Plus, Nature Made), and 2,400 mg red yeast rice (Arazo Nutrition).

Adherence to the assigned regimens was high, Dr. Laffin said, given that only four participants took less than 70% of their assigned doses.

Levels of LDL cholesterol in the statin group fell by 37.9% in 28 days, and by 35.2% relative to the placebo group (P < .001 for both differences), whereas any changes in LDL cholesterol among patients taking the most supplements were not significantly different from the placebo group. Of note, LDL cholesterol levels rose 7.8% (P = .01) compared with placebo among the group assigned to the garlic supplement.

Rosuvastatin had no apparent effect on HDL cholesterol levels, nor did most of the supplements; but such levels in patients taking the plant sterol supplement decreased by 7.1% (P = .02) compared to placebo and by 4% (P = .01) compared to the statin group.

None of the noncontrol groups, including those assigned to rosuvastatin, showed significant changes in high-sensitivity CRP levels compared with the placebo group. The lack of rosuvastatin effect on the inflammatory biomarker, the researchers speculated, is probably explained by the statins’ low dose as well as the limited size of the trial population.

There were two serious adverse events, including one deep venous thrombosis in the placebo group and a liver adenocarcinoma in a patient assigned to fish oil who “had not yet taken any of the study drug at the time of the serious adverse event,” the published report notes.
It remains open whether any of the assigned regimens could show different results over the long term, Dr. Laffin said. The SPORT trial’s 28-day duration, he said, “may not have fully captured the impact of supplements on lipid and inflammatory biomarkers.”

Nor is it known whether the supplements can potentially affect clinical outcomes. But “you could make an argument that it would be unethical” to randomize similar patients to a placebo-controlled, cardiovascular outcomes trial comparing the same six supplements and a statin.

Dr. Laffin has disclosed consulting or serving on a steering committee for Medtronic, Lilly, Mineralys Therapeutics, AstraZeneca, and Crispr Therapeutics; receiving research funding from AstraZeneca; and having ownership interest in LucidAct Health and Gordy Health. Dr. Ndumele and Dr. Khera have reported no relevant financial relationships.

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

CHICAGO – None of six commercial dietary supplements widely promoted and taken for lowering LDL cholesterol did the job any better than placebo in a randomized trial of adults without cardiovascular disease but at increased cardiovascular risk.

In contrast, those who took the low dose of a high-potency statin in the eight-arm comparative study showed a significant 38% drop in LDL cholesterol levels over 28 days, a performance that blew away the six supplements containing fish oil, cinnamon, garlic, turmeric, plant sterols, or red yeast rice.

The supplements showed little or no effect on any measured lipid biomarkers, which also included total cholesterol and triglycerides, or C-reactive protein (CRP), which reflects systemic inflammation.

The findings undercut the widespread heart-health marketing claims for such supplements and could potentially restore faith in statins for the many patients looking for alternatives, researchers say.

“We all see patients that have their medication lists littered with dietary supplements,” observed Luke J. Laffin, MD, of the Cleveland Clinic Foundation. And it’s more than just heart patients who use them.

Almost $50 billion is spent on dietary supplements annually in the United States, and recent data suggest that more than three-fourths of the population use them, 18% of those based on specious heart-health claims, Dr. Laffin said in a Nov. 6 presentation at the American Heart Association scientific sessions.

The findings of the Supplements, Placebo, or Rosuvastatin Study (SPORT) and how they are framed for the public “are important for public health,” he said.

“As cardiologists, primary care doctors, and others, we really should use these results to have evidence-based discussions with patients” regarding the value of even low-dose statins and the supplements’ “lack of benefit,” said Dr. Laffin, lead author on the SPORT publication, which was published the same day in the Journal of the American College of Cardiology.

Patients assigned to low-dose rosuvastatin showed a mean 24.4% drop in total cholesterol levels over 28 days, the study’s primary endpoint. That differed from the placebo group and those for each supplement at P < .001.

They also averaged a 19.2% decrease in serum triglycerides, P < .05 for all group comparisons. None of the six supplements was significantly different from placebo for change in levels of either total cholesterol or triglycerides.

Nor were there significant differences in adverse events across the groups; there were no adverse changes in liver or kidney function tests or glucose levels; and there were no signs of musculoskeletal symptoms, the published report notes.
 

How to message the results

The SPORT trial is valuable for “addressing the void of data on supplements and cardiovascular health,” Chiadi E. Ndumele, MD, PhD, Johns Hopkins University, Baltimore, said as the invited discussant following Dr. Laffin’s presentation.

But they also send a reassuring message about statins, he noted. In a recent study of statin-nonadherent patients, 80% “were worried about statin side effects as the primary reason for not taking their statin, and 72% preferred using natural supplements instead of taking their prescription therapy,” Dr. Ndumele said. “The reason for this is clearly mistrust, misinformation, and a lack of evidence.”

The next step, he proposed, should be to get the study’s positive message about statins to the public, and especially patients “who are hesitant about statin use.” The current study “underscores the fact that using a low dose of a high-potency statin is associated with a very, very low risk of side effects.”

At a media briefing on SPORT, Amit Khera, MD, agreed the randomized trial provides some needed evidence that can be discussed with patients. “If someone’s coming to see me for cholesterol, we can say definitively now, at least there is data that these [supplements] don’t help your cholesterol and statins do.” Dr. Khera directs the preventive cardiology program at University of Texas Southwestern Medical Center, Dallas.

“I think for those who are there very specifically to lower their cholesterol, hopefully this will resonate,” he said.

“I personally didn’t see a lot of harms in using these supplements. But I also didn’t see any benefits,” Dr. Khera told this news organization.

“Now, if you’re taking them for other reasons, so be it. But if you need to lower your cholesterol for cardiovascular health reasons,” he said, “you need to know that they are minimally to not effective at all.”

But such supplements still “are not without harm,” Dr. Laffin proposed at the press conference. For example, they have potential for drug-drug interactions, “not only with cardiovascular medicines, but those taken for other reasons,” he said. “There are 90,000 supplements on the market in the United States today, and there are all kinds of potential safety issues associated with them.”

In patient discussions, Dr. Laffin said, “I do not think it’s good enough to say, you can waste your money [on supplements] as long as you’re taking your statin. These can actually be harmful in certain situations.”

SPORT, described as a single-center study, randomly assigned 199 participants from “throughout the Cleveland Clinic Health System in northeast Ohio” to one of the eight treatment groups. The investigators were blinded to treatment assignments, Dr. Laffin reported.
 

High adherence

Entry criteria included age 40 to 75 years with no history of cardiovascular disease, LDL-cholesterol from 70 to 189 mg/dL, and a 5%-20% 10-year risk of atherosclerotic cardiovascular disease by the pooled cohort equations. The predominantly White cohort averaged 64.4 years in age and 59% were women.

They were assigned to receive rosuvastatin 5 mg daily, placebo, or daily doses of supplements, with 25 patients per group, except the fish-oil group, which comprised 24 patients.

The daily supplement dosages were 2,400 mg for fish oil (Nature Made); 2,400 mg for cinnamon (NutriFlair), 5,000 mcg allicin for the garlic (Garlique), 4,500 mg for turmeric curcumin (BioSchwartz), 1,600 mg plant sterols (CholestOff Plus, Nature Made), and 2,400 mg red yeast rice (Arazo Nutrition).

Adherence to the assigned regimens was high, Dr. Laffin said, given that only four participants took less than 70% of their assigned doses.

Levels of LDL cholesterol in the statin group fell by 37.9% in 28 days, and by 35.2% relative to the placebo group (P < .001 for both differences), whereas any changes in LDL cholesterol among patients taking the most supplements were not significantly different from the placebo group. Of note, LDL cholesterol levels rose 7.8% (P = .01) compared with placebo among the group assigned to the garlic supplement.

Rosuvastatin had no apparent effect on HDL cholesterol levels, nor did most of the supplements; but such levels in patients taking the plant sterol supplement decreased by 7.1% (P = .02) compared to placebo and by 4% (P = .01) compared to the statin group.

None of the noncontrol groups, including those assigned to rosuvastatin, showed significant changes in high-sensitivity CRP levels compared with the placebo group. The lack of rosuvastatin effect on the inflammatory biomarker, the researchers speculated, is probably explained by the statins’ low dose as well as the limited size of the trial population.

There were two serious adverse events, including one deep venous thrombosis in the placebo group and a liver adenocarcinoma in a patient assigned to fish oil who “had not yet taken any of the study drug at the time of the serious adverse event,” the published report notes.
It remains open whether any of the assigned regimens could show different results over the long term, Dr. Laffin said. The SPORT trial’s 28-day duration, he said, “may not have fully captured the impact of supplements on lipid and inflammatory biomarkers.”

Nor is it known whether the supplements can potentially affect clinical outcomes. But “you could make an argument that it would be unethical” to randomize similar patients to a placebo-controlled, cardiovascular outcomes trial comparing the same six supplements and a statin.

Dr. Laffin has disclosed consulting or serving on a steering committee for Medtronic, Lilly, Mineralys Therapeutics, AstraZeneca, and Crispr Therapeutics; receiving research funding from AstraZeneca; and having ownership interest in LucidAct Health and Gordy Health. Dr. Ndumele and Dr. Khera have reported no relevant financial relationships.

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

CHICAGO – None of six commercial dietary supplements widely promoted and taken for lowering LDL cholesterol did the job any better than placebo in a randomized trial of adults without cardiovascular disease but at increased cardiovascular risk.

In contrast, those who took the low dose of a high-potency statin in the eight-arm comparative study showed a significant 38% drop in LDL cholesterol levels over 28 days, a performance that blew away the six supplements containing fish oil, cinnamon, garlic, turmeric, plant sterols, or red yeast rice.

The supplements showed little or no effect on any measured lipid biomarkers, which also included total cholesterol and triglycerides, or C-reactive protein (CRP), which reflects systemic inflammation.

The findings undercut the widespread heart-health marketing claims for such supplements and could potentially restore faith in statins for the many patients looking for alternatives, researchers say.

“We all see patients that have their medication lists littered with dietary supplements,” observed Luke J. Laffin, MD, of the Cleveland Clinic Foundation. And it’s more than just heart patients who use them.

Almost $50 billion is spent on dietary supplements annually in the United States, and recent data suggest that more than three-fourths of the population use them, 18% of those based on specious heart-health claims, Dr. Laffin said in a Nov. 6 presentation at the American Heart Association scientific sessions.

The findings of the Supplements, Placebo, or Rosuvastatin Study (SPORT) and how they are framed for the public “are important for public health,” he said.

“As cardiologists, primary care doctors, and others, we really should use these results to have evidence-based discussions with patients” regarding the value of even low-dose statins and the supplements’ “lack of benefit,” said Dr. Laffin, lead author on the SPORT publication, which was published the same day in the Journal of the American College of Cardiology.

Patients assigned to low-dose rosuvastatin showed a mean 24.4% drop in total cholesterol levels over 28 days, the study’s primary endpoint. That differed from the placebo group and those for each supplement at P < .001.

They also averaged a 19.2% decrease in serum triglycerides, P < .05 for all group comparisons. None of the six supplements was significantly different from placebo for change in levels of either total cholesterol or triglycerides.

Nor were there significant differences in adverse events across the groups; there were no adverse changes in liver or kidney function tests or glucose levels; and there were no signs of musculoskeletal symptoms, the published report notes.
 

How to message the results

The SPORT trial is valuable for “addressing the void of data on supplements and cardiovascular health,” Chiadi E. Ndumele, MD, PhD, Johns Hopkins University, Baltimore, said as the invited discussant following Dr. Laffin’s presentation.

But they also send a reassuring message about statins, he noted. In a recent study of statin-nonadherent patients, 80% “were worried about statin side effects as the primary reason for not taking their statin, and 72% preferred using natural supplements instead of taking their prescription therapy,” Dr. Ndumele said. “The reason for this is clearly mistrust, misinformation, and a lack of evidence.”

The next step, he proposed, should be to get the study’s positive message about statins to the public, and especially patients “who are hesitant about statin use.” The current study “underscores the fact that using a low dose of a high-potency statin is associated with a very, very low risk of side effects.”

At a media briefing on SPORT, Amit Khera, MD, agreed the randomized trial provides some needed evidence that can be discussed with patients. “If someone’s coming to see me for cholesterol, we can say definitively now, at least there is data that these [supplements] don’t help your cholesterol and statins do.” Dr. Khera directs the preventive cardiology program at University of Texas Southwestern Medical Center, Dallas.

“I think for those who are there very specifically to lower their cholesterol, hopefully this will resonate,” he said.

“I personally didn’t see a lot of harms in using these supplements. But I also didn’t see any benefits,” Dr. Khera told this news organization.

“Now, if you’re taking them for other reasons, so be it. But if you need to lower your cholesterol for cardiovascular health reasons,” he said, “you need to know that they are minimally to not effective at all.”

But such supplements still “are not without harm,” Dr. Laffin proposed at the press conference. For example, they have potential for drug-drug interactions, “not only with cardiovascular medicines, but those taken for other reasons,” he said. “There are 90,000 supplements on the market in the United States today, and there are all kinds of potential safety issues associated with them.”

In patient discussions, Dr. Laffin said, “I do not think it’s good enough to say, you can waste your money [on supplements] as long as you’re taking your statin. These can actually be harmful in certain situations.”

SPORT, described as a single-center study, randomly assigned 199 participants from “throughout the Cleveland Clinic Health System in northeast Ohio” to one of the eight treatment groups. The investigators were blinded to treatment assignments, Dr. Laffin reported.
 

High adherence

Entry criteria included age 40 to 75 years with no history of cardiovascular disease, LDL-cholesterol from 70 to 189 mg/dL, and a 5%-20% 10-year risk of atherosclerotic cardiovascular disease by the pooled cohort equations. The predominantly White cohort averaged 64.4 years in age and 59% were women.

They were assigned to receive rosuvastatin 5 mg daily, placebo, or daily doses of supplements, with 25 patients per group, except the fish-oil group, which comprised 24 patients.

The daily supplement dosages were 2,400 mg for fish oil (Nature Made); 2,400 mg for cinnamon (NutriFlair), 5,000 mcg allicin for the garlic (Garlique), 4,500 mg for turmeric curcumin (BioSchwartz), 1,600 mg plant sterols (CholestOff Plus, Nature Made), and 2,400 mg red yeast rice (Arazo Nutrition).

Adherence to the assigned regimens was high, Dr. Laffin said, given that only four participants took less than 70% of their assigned doses.

Levels of LDL cholesterol in the statin group fell by 37.9% in 28 days, and by 35.2% relative to the placebo group (P < .001 for both differences), whereas any changes in LDL cholesterol among patients taking the most supplements were not significantly different from the placebo group. Of note, LDL cholesterol levels rose 7.8% (P = .01) compared with placebo among the group assigned to the garlic supplement.

Rosuvastatin had no apparent effect on HDL cholesterol levels, nor did most of the supplements; but such levels in patients taking the plant sterol supplement decreased by 7.1% (P = .02) compared to placebo and by 4% (P = .01) compared to the statin group.

None of the noncontrol groups, including those assigned to rosuvastatin, showed significant changes in high-sensitivity CRP levels compared with the placebo group. The lack of rosuvastatin effect on the inflammatory biomarker, the researchers speculated, is probably explained by the statins’ low dose as well as the limited size of the trial population.

There were two serious adverse events, including one deep venous thrombosis in the placebo group and a liver adenocarcinoma in a patient assigned to fish oil who “had not yet taken any of the study drug at the time of the serious adverse event,” the published report notes.
It remains open whether any of the assigned regimens could show different results over the long term, Dr. Laffin said. The SPORT trial’s 28-day duration, he said, “may not have fully captured the impact of supplements on lipid and inflammatory biomarkers.”

Nor is it known whether the supplements can potentially affect clinical outcomes. But “you could make an argument that it would be unethical” to randomize similar patients to a placebo-controlled, cardiovascular outcomes trial comparing the same six supplements and a statin.

Dr. Laffin has disclosed consulting or serving on a steering committee for Medtronic, Lilly, Mineralys Therapeutics, AstraZeneca, and Crispr Therapeutics; receiving research funding from AstraZeneca; and having ownership interest in LucidAct Health and Gordy Health. Dr. Ndumele and Dr. Khera have reported no relevant financial relationships.

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

Brain wave recordings obtained during cardiopulmonary resuscitation (CPR) offer support to near-death experiences subjectively reported by some people who survive cardiac arrest, according to a novel new study.

“These recalled experiences and brain wave changes may be the first signs of the so-called ‘near-death’ experience, and we have captured them for the first time in a large study,” lead investigator Sam Parnia, MD, PhD, with NYU Langone Health, said in a news release.

Identifying measurable electrical signs of lucid and heightened brain activity during CPR, coupled with stories of recalled near-death experiences, suggests that the human sense of self and consciousness, much like other biological body functions, may not stop completely around the time of death, Dr. Parnia added.

He presented the findings Nov. 6 at a resuscitation science symposium at the American Heart Association scientific sessions.
 

The AWARE II study

“For years, some people in cardiac arrest have reported being lucid, often with a heightened sense of consciousness, while seemingly unconscious and on the brink of death,” Dr. Parnia noted in an interview.

“Yet, no one’s ever be able to prove it and a lot of people have dismissed these experiences, thinking it’s all just a trick on the brain,” Dr. Parnia said.

In a first-of-its-kind study, Dr. Parnia and colleagues examined consciousness and its underlying electrocortical biomarkers during CPR for in-hospital cardiac arrest (IHCA).

They incorporated independent audiovisual testing of awareness with continuous real-time EEG and cerebral oxygenation (rSO₂) monitoring into CPR.

Only 53 of the 567 IHCA patients survived (9.3%). Among the 28 (52.8%) IHCA survivors who completed interviews, 11 (39.3%) reported unique, lucid experiences during resuscitation.

These experiences included a perception of separation from one’s body, observing events without pain or distress, and an awareness and meaningful evaluation of life, including of their actions, intentions, and thoughts toward others.

“These lucid experiences of death are not hallucinations or delusions. They cannot be considered a trick of a disordered or dying brain, but rather a unique human experience that emerges on the brink of death,” Dr. Parnia said. 

And what’s “fascinating,” he added, is that despite marked cerebral ischemia (mean regional oxygen saturation [rSO₂]  43%), near-normal/physiologic EEG activity (gamma, delta, theta, alpha, and beta rhythms) consistent with consciousness and a possible resumption of a network-level of cognitive and neuronal activity emerged for as long as 35-60 minutes into CPR.

Some of these brain waves normally occur when people are conscious and performing higher mental functions, including thinking, memory retrieval, and conscious perception, he said.
 

‘Seismic shift’ in understanding of death

This is the first time such biomarkers of consciousness have been identified during cardiac arrest and CPR, Dr. Parnia said.

He said further study is needed to more precisely define biomarkers of what is considered to be clinical consciousness and the recalled experience of death, and to monitor the long-term psychological effects of resuscitation after cardiac arrest.

“Our understanding of death has gone through a seismic shift in the last few years,” he said.

“The biological discoveries around death and the postmortem period are completely different to the social conventions that we have about death. That is, we perceive of death as being the end, but actually what we’re finding is that brain cells don’t die immediately. They die very slowly over many hours of time,” Dr. Parnia noted.

Reached for comment, Ajmal Zemmar, MD, PhD, of University of Louisville (Ky.), noted that several studies, including this one, “challenge the traditional way that we think of death – that when the heart stops beating that’s when we die.”

The observation that during cardiac arrest and CPR, the brain waves are still normal for up to an hour is “fairly remarkable,” Dr. Zemmar told this news organization.

“However, whether there is conscious perception or not is very hard to answer,” he cautioned. 

“This type of research tries to bridge the objective EEG recordings with the subjective description you get from the patient, but it’s hard to know when conscious perception stops,” he said.

Funding and support for the study were provided by NYU Langone Health, The John Templeton Foundation, and the UK Resuscitation Council, and National Institutes for Health Research. Dr. Parnia and Dr. Zemmar reported no relevant financial relationships.

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

Brain wave recordings obtained during cardiopulmonary resuscitation (CPR) offer support to near-death experiences subjectively reported by some people who survive cardiac arrest, according to a novel new study.

“These recalled experiences and brain wave changes may be the first signs of the so-called ‘near-death’ experience, and we have captured them for the first time in a large study,” lead investigator Sam Parnia, MD, PhD, with NYU Langone Health, said in a news release.

Identifying measurable electrical signs of lucid and heightened brain activity during CPR, coupled with stories of recalled near-death experiences, suggests that the human sense of self and consciousness, much like other biological body functions, may not stop completely around the time of death, Dr. Parnia added.

He presented the findings Nov. 6 at a resuscitation science symposium at the American Heart Association scientific sessions.
 

The AWARE II study

“For years, some people in cardiac arrest have reported being lucid, often with a heightened sense of consciousness, while seemingly unconscious and on the brink of death,” Dr. Parnia noted in an interview.

“Yet, no one’s ever be able to prove it and a lot of people have dismissed these experiences, thinking it’s all just a trick on the brain,” Dr. Parnia said.

In a first-of-its-kind study, Dr. Parnia and colleagues examined consciousness and its underlying electrocortical biomarkers during CPR for in-hospital cardiac arrest (IHCA).

They incorporated independent audiovisual testing of awareness with continuous real-time EEG and cerebral oxygenation (rSO₂) monitoring into CPR.

Only 53 of the 567 IHCA patients survived (9.3%). Among the 28 (52.8%) IHCA survivors who completed interviews, 11 (39.3%) reported unique, lucid experiences during resuscitation.

These experiences included a perception of separation from one’s body, observing events without pain or distress, and an awareness and meaningful evaluation of life, including of their actions, intentions, and thoughts toward others.

“These lucid experiences of death are not hallucinations or delusions. They cannot be considered a trick of a disordered or dying brain, but rather a unique human experience that emerges on the brink of death,” Dr. Parnia said. 

And what’s “fascinating,” he added, is that despite marked cerebral ischemia (mean regional oxygen saturation [rSO₂]  43%), near-normal/physiologic EEG activity (gamma, delta, theta, alpha, and beta rhythms) consistent with consciousness and a possible resumption of a network-level of cognitive and neuronal activity emerged for as long as 35-60 minutes into CPR.

Some of these brain waves normally occur when people are conscious and performing higher mental functions, including thinking, memory retrieval, and conscious perception, he said.
 

‘Seismic shift’ in understanding of death

This is the first time such biomarkers of consciousness have been identified during cardiac arrest and CPR, Dr. Parnia said.

He said further study is needed to more precisely define biomarkers of what is considered to be clinical consciousness and the recalled experience of death, and to monitor the long-term psychological effects of resuscitation after cardiac arrest.

“Our understanding of death has gone through a seismic shift in the last few years,” he said.

“The biological discoveries around death and the postmortem period are completely different to the social conventions that we have about death. That is, we perceive of death as being the end, but actually what we’re finding is that brain cells don’t die immediately. They die very slowly over many hours of time,” Dr. Parnia noted.

Reached for comment, Ajmal Zemmar, MD, PhD, of University of Louisville (Ky.), noted that several studies, including this one, “challenge the traditional way that we think of death – that when the heart stops beating that’s when we die.”

The observation that during cardiac arrest and CPR, the brain waves are still normal for up to an hour is “fairly remarkable,” Dr. Zemmar told this news organization.

“However, whether there is conscious perception or not is very hard to answer,” he cautioned. 

“This type of research tries to bridge the objective EEG recordings with the subjective description you get from the patient, but it’s hard to know when conscious perception stops,” he said.

Funding and support for the study were provided by NYU Langone Health, The John Templeton Foundation, and the UK Resuscitation Council, and National Institutes for Health Research. Dr. Parnia and Dr. Zemmar reported no relevant financial relationships.

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

Brain wave recordings obtained during cardiopulmonary resuscitation (CPR) offer support to near-death experiences subjectively reported by some people who survive cardiac arrest, according to a novel new study.

“These recalled experiences and brain wave changes may be the first signs of the so-called ‘near-death’ experience, and we have captured them for the first time in a large study,” lead investigator Sam Parnia, MD, PhD, with NYU Langone Health, said in a news release.

Identifying measurable electrical signs of lucid and heightened brain activity during CPR, coupled with stories of recalled near-death experiences, suggests that the human sense of self and consciousness, much like other biological body functions, may not stop completely around the time of death, Dr. Parnia added.

He presented the findings Nov. 6 at a resuscitation science symposium at the American Heart Association scientific sessions.
 

The AWARE II study

“For years, some people in cardiac arrest have reported being lucid, often with a heightened sense of consciousness, while seemingly unconscious and on the brink of death,” Dr. Parnia noted in an interview.

“Yet, no one’s ever be able to prove it and a lot of people have dismissed these experiences, thinking it’s all just a trick on the brain,” Dr. Parnia said.

In a first-of-its-kind study, Dr. Parnia and colleagues examined consciousness and its underlying electrocortical biomarkers during CPR for in-hospital cardiac arrest (IHCA).

They incorporated independent audiovisual testing of awareness with continuous real-time EEG and cerebral oxygenation (rSO₂) monitoring into CPR.

Only 53 of the 567 IHCA patients survived (9.3%). Among the 28 (52.8%) IHCA survivors who completed interviews, 11 (39.3%) reported unique, lucid experiences during resuscitation.

These experiences included a perception of separation from one’s body, observing events without pain or distress, and an awareness and meaningful evaluation of life, including of their actions, intentions, and thoughts toward others.

“These lucid experiences of death are not hallucinations or delusions. They cannot be considered a trick of a disordered or dying brain, but rather a unique human experience that emerges on the brink of death,” Dr. Parnia said. 

And what’s “fascinating,” he added, is that despite marked cerebral ischemia (mean regional oxygen saturation [rSO₂]  43%), near-normal/physiologic EEG activity (gamma, delta, theta, alpha, and beta rhythms) consistent with consciousness and a possible resumption of a network-level of cognitive and neuronal activity emerged for as long as 35-60 minutes into CPR.

Some of these brain waves normally occur when people are conscious and performing higher mental functions, including thinking, memory retrieval, and conscious perception, he said.
 

‘Seismic shift’ in understanding of death

This is the first time such biomarkers of consciousness have been identified during cardiac arrest and CPR, Dr. Parnia said.

He said further study is needed to more precisely define biomarkers of what is considered to be clinical consciousness and the recalled experience of death, and to monitor the long-term psychological effects of resuscitation after cardiac arrest.

“Our understanding of death has gone through a seismic shift in the last few years,” he said.

“The biological discoveries around death and the postmortem period are completely different to the social conventions that we have about death. That is, we perceive of death as being the end, but actually what we’re finding is that brain cells don’t die immediately. They die very slowly over many hours of time,” Dr. Parnia noted.

Reached for comment, Ajmal Zemmar, MD, PhD, of University of Louisville (Ky.), noted that several studies, including this one, “challenge the traditional way that we think of death – that when the heart stops beating that’s when we die.”

The observation that during cardiac arrest and CPR, the brain waves are still normal for up to an hour is “fairly remarkable,” Dr. Zemmar told this news organization.

“However, whether there is conscious perception or not is very hard to answer,” he cautioned. 

“This type of research tries to bridge the objective EEG recordings with the subjective description you get from the patient, but it’s hard to know when conscious perception stops,” he said.

Funding and support for the study were provided by NYU Langone Health, The John Templeton Foundation, and the UK Resuscitation Council, and National Institutes for Health Research. Dr. Parnia and Dr. Zemmar reported no relevant financial relationships.

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