Conference Coverage

In patients hospitalized with COVID-19 infection, the sodium-glucose transporter 2 inhibitor dapagliflozin showed a trend for benefit relative to placebo on multiple outcomes, including the primary outcome of time to organ failure or death, according to results from the randomized DARE-19 trial.

Because of the failure to reach statistical significance, these results have no immediate relevance, but the trends support interest in further testing SGLT2 inhibitors in acute diseases posing a high risk for organ failure, according to Mikhail Kosiborod, MD.

In a trial that did not meet its primary endpoint, Dr. Kosiborod acknowledged that positive interpretations are speculative, but he does believe that there is one immediate take-home message.

“Our results do not support discontinuation of SGLT2 inhibitors in the setting of COVID-19 as long as patients are monitored,” said Dr. Kosiborod, director of cardiometabolic research at Saint Luke’s Mid-America Heart Institute, Kansas City, Mo.

At many institutions, it has been common to discontinue SGLT2 inhibitors in patients admitted with COVID-19. One reason was the concern that drugs in this class could exacerbate organ damage, particularly if they were to induced ketoacidosis. However, only 2 (0.003%) of 613 patients treated with dapagliflozin developed ketoacidosis, and the signal for organ protection overall, although not significant, was consistent.

“Numerically, fewer patients treated with dapagliflozin experienced organ failure and death, and this was consistent across systems, including the kidney,” Dr. Kosiborod said in presenting the study at the annual scientific sessions of the American College of Cardiology.

Overall, the study suggests that, in the context of COVID-19, dapagliflozin did not show harm and might have potential benefit, he added.

DARE-19 was rapidly conceived, designed, and implemented during the early stages of the COVID-19 pandemic. Based on prior evidence that SGLT2 inhibitors “favorably affect a number of pathophysiologic pathways disrupted during acute illness” and that drugs in this class have provided organ protection in the context of heart failure, chronic kidney disease, and other cardiometabolic conditions, the study was designed to test the hypothesis that this mechanism might improve outcomes in patients hospitalized with COVID-19, Dr. Kosiborod said.

The entry criteria included confirmed or suspected COVID-19 with an onset of 4 days of fewer and one additional risk factor, such as atherosclerotic cardiovascular disease, hypertension, or type 2 diabetes. Patients with significant renal impairment or a history of diabetic ketoacidosis were excluded.

On top of standard treatments for COVID-19, patients were randomized to 10 mg dapagliflozin or placebo once daily. There were two primary endpoints. That of prevention was time to criteria for respiratory, cardiovascular, or renal organ failure or death. The second primary outcome, for recovery, was a hierarchical composite for four endpoints: death, organ failure, status at 30 days if hospitalized, and time to discharge if this occurred before day 30.

Of the 1,250 patients randomized at 95 sites in seven countries, 617 in the dapagliflozin group and 620 patients in the placebo group completed the study. Baseline characteristics, which included a mean of age of 62 years; types of comorbidities; and types of treatments were similar.
 

Results for two primary endpoints

The curves for the primary outcome of prevention had already separated by day 3 and continued to widen over the 30 days in which outcomes were compared. At the end of 30 days, 11.2% of the dapagliflozin group and 13.8% of the placebo group had an event. By hazard ratio, dapagliflozin was linked to 20% nonsignificant relative protection from events (hazard ratio, 0.80; 95% confidence interval, 0.58-1.10).

The trend (P = .168) for the primary endpoint for prevention was reflected in the individual components. For dapagliflozin related to placebo, there were generally similar or greater reductions in new or worsening organ failure (HR, 0.80), cardiac decompensation (HR, 0.81), respiratory decompensation (HR, 0.85), and kidney decompensation (HR, 0.65). None were statistically significant, but the confidence intervals were tight with the upper end never exceeding 1.20.

Moreover, the relative risk reduction for all-cause mortality moved in the same direction (HR, 0.77; 95% CI, 0.52-1.16).

In the hierarchical composite endpoint of recovery, there was no significant difference in the time to discharge, but again many recovery metrics numerically favored dapagliflozin with an overall difference producing a statistical trend (P = .14) similar to organ failure events and death.

In safety analyses, dapagliflozin consistently outperformed placebo across a broad array of safety measure, including any severe adverse event (65% vs. 82%), any adverse event with an outcome of death (32% vs. 48%), discontinuation caused by an adverse event (44% vs. 55%), and acute kidney injury (21% vs. 34%).
 

Data could fuel related studies

According to Ana Barac, MD, PhD, director of the cardio-oncology program in the Medstar Heart and Vascular Institute, Washington, these data are “thought provoking.” Although this was a negative trial, she said that it generates an “exciting hypothesis” about the potential of SGLT2 inhibitors to provide organ protection. She called for studies to pursue this path of research.

More immediately, Dr. Barac agreed that these data argue against stopping SGLT2 inhibitors in patients admitted to a hospital for COVID-19 infection.

“These data show that these drugs are not going to lead to harm, but they might lead to benefit,” she said.

For James Januzzi, MD, a cardiologist at Massachusetts General Hospital and professor of medicine at Harvard Medical School, both in Boston, DARE-19 was perhaps most impressive because of its rigorous design and execution in the midst of a pandemic.

Over the past year, “the medical literature was flooded with grossly underpowered, poorly designed, single-center studies” yielding results that have been hard to interpret, Dr. Januzzi said. Despite the fact that this study failed to confirm its hypothesis, he said the investigators deserve praise for the quality of the work.

Courtesy Massachusetts General Hospital

Dr. Januzzi also believes the study is not without clinically relevant findings, particularly the fact that dapagliflozin was associated with a lower rate of adverse events than placebo. This, at least, provides reassurance about the safety of this drug in the setting of COVID-19 infection.

Dr. Kosiborod reported financial relationships with more than 10 pharmaceutical companies, including AstraZeneca, which provided funding for DARE-19. Dr. Barac reported financial relationships with Bristol-Myers Squibb and CTI BioPharma. Dr. Januzzi reported financial relationships with Boehringer Ingelheim, GE Healthcare, Johnson & Johnson, Merck, Novartis, Pfizer, and Roche.

In patients hospitalized with COVID-19 infection, the sodium-glucose transporter 2 inhibitor dapagliflozin showed a trend for benefit relative to placebo on multiple outcomes, including the primary outcome of time to organ failure or death, according to results from the randomized DARE-19 trial.

Because of the failure to reach statistical significance, these results have no immediate relevance, but the trends support interest in further testing SGLT2 inhibitors in acute diseases posing a high risk for organ failure, according to Mikhail Kosiborod, MD.

In a trial that did not meet its primary endpoint, Dr. Kosiborod acknowledged that positive interpretations are speculative, but he does believe that there is one immediate take-home message.

“Our results do not support discontinuation of SGLT2 inhibitors in the setting of COVID-19 as long as patients are monitored,” said Dr. Kosiborod, director of cardiometabolic research at Saint Luke’s Mid-America Heart Institute, Kansas City, Mo.

At many institutions, it has been common to discontinue SGLT2 inhibitors in patients admitted with COVID-19. One reason was the concern that drugs in this class could exacerbate organ damage, particularly if they were to induced ketoacidosis. However, only 2 (0.003%) of 613 patients treated with dapagliflozin developed ketoacidosis, and the signal for organ protection overall, although not significant, was consistent.

“Numerically, fewer patients treated with dapagliflozin experienced organ failure and death, and this was consistent across systems, including the kidney,” Dr. Kosiborod said in presenting the study at the annual scientific sessions of the American College of Cardiology.

Overall, the study suggests that, in the context of COVID-19, dapagliflozin did not show harm and might have potential benefit, he added.

DARE-19 was rapidly conceived, designed, and implemented during the early stages of the COVID-19 pandemic. Based on prior evidence that SGLT2 inhibitors “favorably affect a number of pathophysiologic pathways disrupted during acute illness” and that drugs in this class have provided organ protection in the context of heart failure, chronic kidney disease, and other cardiometabolic conditions, the study was designed to test the hypothesis that this mechanism might improve outcomes in patients hospitalized with COVID-19, Dr. Kosiborod said.

The entry criteria included confirmed or suspected COVID-19 with an onset of 4 days of fewer and one additional risk factor, such as atherosclerotic cardiovascular disease, hypertension, or type 2 diabetes. Patients with significant renal impairment or a history of diabetic ketoacidosis were excluded.

On top of standard treatments for COVID-19, patients were randomized to 10 mg dapagliflozin or placebo once daily. There were two primary endpoints. That of prevention was time to criteria for respiratory, cardiovascular, or renal organ failure or death. The second primary outcome, for recovery, was a hierarchical composite for four endpoints: death, organ failure, status at 30 days if hospitalized, and time to discharge if this occurred before day 30.

Of the 1,250 patients randomized at 95 sites in seven countries, 617 in the dapagliflozin group and 620 patients in the placebo group completed the study. Baseline characteristics, which included a mean of age of 62 years; types of comorbidities; and types of treatments were similar.
 

Results for two primary endpoints

The curves for the primary outcome of prevention had already separated by day 3 and continued to widen over the 30 days in which outcomes were compared. At the end of 30 days, 11.2% of the dapagliflozin group and 13.8% of the placebo group had an event. By hazard ratio, dapagliflozin was linked to 20% nonsignificant relative protection from events (hazard ratio, 0.80; 95% confidence interval, 0.58-1.10).

The trend (P = .168) for the primary endpoint for prevention was reflected in the individual components. For dapagliflozin related to placebo, there were generally similar or greater reductions in new or worsening organ failure (HR, 0.80), cardiac decompensation (HR, 0.81), respiratory decompensation (HR, 0.85), and kidney decompensation (HR, 0.65). None were statistically significant, but the confidence intervals were tight with the upper end never exceeding 1.20.

Moreover, the relative risk reduction for all-cause mortality moved in the same direction (HR, 0.77; 95% CI, 0.52-1.16).

In the hierarchical composite endpoint of recovery, there was no significant difference in the time to discharge, but again many recovery metrics numerically favored dapagliflozin with an overall difference producing a statistical trend (P = .14) similar to organ failure events and death.

In safety analyses, dapagliflozin consistently outperformed placebo across a broad array of safety measure, including any severe adverse event (65% vs. 82%), any adverse event with an outcome of death (32% vs. 48%), discontinuation caused by an adverse event (44% vs. 55%), and acute kidney injury (21% vs. 34%).
 

Data could fuel related studies

According to Ana Barac, MD, PhD, director of the cardio-oncology program in the Medstar Heart and Vascular Institute, Washington, these data are “thought provoking.” Although this was a negative trial, she said that it generates an “exciting hypothesis” about the potential of SGLT2 inhibitors to provide organ protection. She called for studies to pursue this path of research.

More immediately, Dr. Barac agreed that these data argue against stopping SGLT2 inhibitors in patients admitted to a hospital for COVID-19 infection.

“These data show that these drugs are not going to lead to harm, but they might lead to benefit,” she said.

For James Januzzi, MD, a cardiologist at Massachusetts General Hospital and professor of medicine at Harvard Medical School, both in Boston, DARE-19 was perhaps most impressive because of its rigorous design and execution in the midst of a pandemic.

Over the past year, “the medical literature was flooded with grossly underpowered, poorly designed, single-center studies” yielding results that have been hard to interpret, Dr. Januzzi said. Despite the fact that this study failed to confirm its hypothesis, he said the investigators deserve praise for the quality of the work.

Courtesy Massachusetts General Hospital

Dr. Januzzi also believes the study is not without clinically relevant findings, particularly the fact that dapagliflozin was associated with a lower rate of adverse events than placebo. This, at least, provides reassurance about the safety of this drug in the setting of COVID-19 infection.

Dr. Kosiborod reported financial relationships with more than 10 pharmaceutical companies, including AstraZeneca, which provided funding for DARE-19. Dr. Barac reported financial relationships with Bristol-Myers Squibb and CTI BioPharma. Dr. Januzzi reported financial relationships with Boehringer Ingelheim, GE Healthcare, Johnson & Johnson, Merck, Novartis, Pfizer, and Roche.

In patients hospitalized with COVID-19 infection, the sodium-glucose transporter 2 inhibitor dapagliflozin showed a trend for benefit relative to placebo on multiple outcomes, including the primary outcome of time to organ failure or death, according to results from the randomized DARE-19 trial.

Because of the failure to reach statistical significance, these results have no immediate relevance, but the trends support interest in further testing SGLT2 inhibitors in acute diseases posing a high risk for organ failure, according to Mikhail Kosiborod, MD.

In a trial that did not meet its primary endpoint, Dr. Kosiborod acknowledged that positive interpretations are speculative, but he does believe that there is one immediate take-home message.

“Our results do not support discontinuation of SGLT2 inhibitors in the setting of COVID-19 as long as patients are monitored,” said Dr. Kosiborod, director of cardiometabolic research at Saint Luke’s Mid-America Heart Institute, Kansas City, Mo.

At many institutions, it has been common to discontinue SGLT2 inhibitors in patients admitted with COVID-19. One reason was the concern that drugs in this class could exacerbate organ damage, particularly if they were to induced ketoacidosis. However, only 2 (0.003%) of 613 patients treated with dapagliflozin developed ketoacidosis, and the signal for organ protection overall, although not significant, was consistent.

“Numerically, fewer patients treated with dapagliflozin experienced organ failure and death, and this was consistent across systems, including the kidney,” Dr. Kosiborod said in presenting the study at the annual scientific sessions of the American College of Cardiology.

Overall, the study suggests that, in the context of COVID-19, dapagliflozin did not show harm and might have potential benefit, he added.

DARE-19 was rapidly conceived, designed, and implemented during the early stages of the COVID-19 pandemic. Based on prior evidence that SGLT2 inhibitors “favorably affect a number of pathophysiologic pathways disrupted during acute illness” and that drugs in this class have provided organ protection in the context of heart failure, chronic kidney disease, and other cardiometabolic conditions, the study was designed to test the hypothesis that this mechanism might improve outcomes in patients hospitalized with COVID-19, Dr. Kosiborod said.

The entry criteria included confirmed or suspected COVID-19 with an onset of 4 days of fewer and one additional risk factor, such as atherosclerotic cardiovascular disease, hypertension, or type 2 diabetes. Patients with significant renal impairment or a history of diabetic ketoacidosis were excluded.

On top of standard treatments for COVID-19, patients were randomized to 10 mg dapagliflozin or placebo once daily. There were two primary endpoints. That of prevention was time to criteria for respiratory, cardiovascular, or renal organ failure or death. The second primary outcome, for recovery, was a hierarchical composite for four endpoints: death, organ failure, status at 30 days if hospitalized, and time to discharge if this occurred before day 30.

Of the 1,250 patients randomized at 95 sites in seven countries, 617 in the dapagliflozin group and 620 patients in the placebo group completed the study. Baseline characteristics, which included a mean of age of 62 years; types of comorbidities; and types of treatments were similar.
 

Results for two primary endpoints

The curves for the primary outcome of prevention had already separated by day 3 and continued to widen over the 30 days in which outcomes were compared. At the end of 30 days, 11.2% of the dapagliflozin group and 13.8% of the placebo group had an event. By hazard ratio, dapagliflozin was linked to 20% nonsignificant relative protection from events (hazard ratio, 0.80; 95% confidence interval, 0.58-1.10).

The trend (P = .168) for the primary endpoint for prevention was reflected in the individual components. For dapagliflozin related to placebo, there were generally similar or greater reductions in new or worsening organ failure (HR, 0.80), cardiac decompensation (HR, 0.81), respiratory decompensation (HR, 0.85), and kidney decompensation (HR, 0.65). None were statistically significant, but the confidence intervals were tight with the upper end never exceeding 1.20.

Moreover, the relative risk reduction for all-cause mortality moved in the same direction (HR, 0.77; 95% CI, 0.52-1.16).

In the hierarchical composite endpoint of recovery, there was no significant difference in the time to discharge, but again many recovery metrics numerically favored dapagliflozin with an overall difference producing a statistical trend (P = .14) similar to organ failure events and death.

In safety analyses, dapagliflozin consistently outperformed placebo across a broad array of safety measure, including any severe adverse event (65% vs. 82%), any adverse event with an outcome of death (32% vs. 48%), discontinuation caused by an adverse event (44% vs. 55%), and acute kidney injury (21% vs. 34%).
 

Data could fuel related studies

According to Ana Barac, MD, PhD, director of the cardio-oncology program in the Medstar Heart and Vascular Institute, Washington, these data are “thought provoking.” Although this was a negative trial, she said that it generates an “exciting hypothesis” about the potential of SGLT2 inhibitors to provide organ protection. She called for studies to pursue this path of research.

More immediately, Dr. Barac agreed that these data argue against stopping SGLT2 inhibitors in patients admitted to a hospital for COVID-19 infection.

“These data show that these drugs are not going to lead to harm, but they might lead to benefit,” she said.

For James Januzzi, MD, a cardiologist at Massachusetts General Hospital and professor of medicine at Harvard Medical School, both in Boston, DARE-19 was perhaps most impressive because of its rigorous design and execution in the midst of a pandemic.

Over the past year, “the medical literature was flooded with grossly underpowered, poorly designed, single-center studies” yielding results that have been hard to interpret, Dr. Januzzi said. Despite the fact that this study failed to confirm its hypothesis, he said the investigators deserve praise for the quality of the work.

Courtesy Massachusetts General Hospital

Dr. Januzzi also believes the study is not without clinically relevant findings, particularly the fact that dapagliflozin was associated with a lower rate of adverse events than placebo. This, at least, provides reassurance about the safety of this drug in the setting of COVID-19 infection.

Dr. Kosiborod reported financial relationships with more than 10 pharmaceutical companies, including AstraZeneca, which provided funding for DARE-19. Dr. Barac reported financial relationships with Bristol-Myers Squibb and CTI BioPharma. Dr. Januzzi reported financial relationships with Boehringer Ingelheim, GE Healthcare, Johnson & Johnson, Merck, Novartis, Pfizer, and Roche.

Treatment with transcranial magnetic stimulation (TMS) has a robust effect for patients with major depressive disorder (MDD), results from a large registry study show.

From patient self-reports and clinician assessments, investigators found that TMS was “surprisingly effective” and “an eye-opener” for these patients, lead investigator Harold A. Sackeim, PhD, professor of clinical psychology in psychiatry and radiology, Columbia University, New York, told this news organization.

“In a presumably treatment-resistant population, the efficacy compared favorably with virtually all pharmacologic treatments” tested in the studies, said Dr. Sackeim.

He noted that the registry from which the data were obtained “is the largest for any treatment of depression, period.” These positive results suggest TMS should be considered a first-line treatment for MDD, he added.

The study was presented at the virtual American Psychiatric Association 2021 Annual Meeting and was previously published in the Journal of Affective Disorders.
 

Real-world study

Results of randomized clinical trials have shown that TMS is effective for episodes of MDD. However, the investigators note that there is a need to characterize and identify patient- and treatment-related clinical outcomes.

The study included 5,010 adult patients who had received a primary diagnosis of MDD and were treated at 103 practices in the United States. Participants completed the nine-item Patient Health Questionnaire (PHQ-9) at baseline and at least one other time following a TMS treatment.

The average baseline PHQ-9 score was 19.8, indicating moderate to severe symptoms. This was also reflected in a smaller sample that included Clinical Global Impressions–Severity (CGI-S) ratings by clinicians, mostly psychiatrists.

About two-thirds of the study population were women. The average age was about 50 years. Participants typically received about 30 TMS sessions over 7 to 8 weeks.

TMS targets tissue in the dorsolateral prefrontal cortex. The standard protocol involves administering “fast” or high-frequency (10-Hz) stimulation on the left side. Sometimes, slow-frequency stimulation on the right side is added. About 57% of patients were treated on the left side, and 43% were treated on both sides. Each session involved delivery of about 3,000 pulses.

In the analysis of patient self-reports (PHQ-9), the response rate, which was defined as resolution of 50% or more of symptoms, was from 58% to 69%. The remission rate, defined as becoming asymptomatic or having minimal symptoms, ranged from 28% to 36%.

Results were about 5% higher in the “completer” sample, which included 3,814 patients who received at least 20 treatments and who completed a PHQ-9 assessment at the end the treatment course.

The number of completers in the analysis was “massive,” said Dr. Sackeim. It’s “ten times larger than in any previous TMS study; all randomized trials have a couple of hundred subjects at most, so this is whopping.”

The results provide “a full snapshot” of TMS in the “real-world” community instead of in the “highly controlled” environment of most studies, he added.
 

Gender differences

The analysis that included CGI-S clinician measures yielded higher outcome estimates – 79% to 83% for the response rate, and 47% to 63% for the remission rate.

Women tended to have better clinical outcomes. “It appears to me that around age 50 is where you see the difference,” said Dr. Sackeim. “Among women, it looks like the older they get, the better the outcome, whereas men are not showing that type of positive aging effect.”

This difference might be due to hormonal changes associated with menopause and the fact that older men with depression may have had a stroke or brain lesion. Dr. Sackeim said he plans to look more closely at outcomes of women in comparison with men.

The finding of a significant positive effect on aging contrasts with earlier research suggesting that age was a negative predictor. This, said Dr. Sackeim, illustrates how rapidly the TMS field is evolving.

He noted that researchers are now personalizing the procedure by determining the optimal target for individual patients. Other investigators are testing different protocols.

In the current study, results tended to be better for those who received 4,000 or more pulses, said Dr. Sackeim. “There was an indication of a dose response effect in terms of how many pulses per session,” he said.

The authors note that the study’s PDQ-9 response and remission rates indicate that clinical outcomes are comparable to those of the seven antidepressants studied in Level 2 of the large Sequenced Treatment Alternatives to Relieve Depression (STAR-D) trial.

Initial data for relapse in the study population are “encouraging,” said Dr. Sackeim. “You don’t see the rapid relapse that you do when you discontinue some treatments, for example with ECT [electroconvulsive therapy].”

The “slower onset of action” over the course of several sessions “may induce longer benefit,” he added.
 

Expanded use warranted?

The intervention proved very safe. Side effects, including headaches, were minimal, and there were “virtually no cognitive effects,” said Dr. Sackeim.

Dr. Sackeim believes TMS, as it has evolved, “is an outstanding option for treatment-resistant depression, and it has a very bright future” and should not be reserved for patients with established treatment-resistant depression (TRD), which is the current U.S. Food and Drug Administration indication.

“Restricting it to TRD in my mind is probably a mistake. Why shouldn’t the patient who is just starting on their course of treatment for depression have this as a nonpharmacological option?” he said.

Limitations of the study included its open-label design and the fact that only patients’ age, gender, outcome scores, and TMS treatment parameters were recorded in the registry. Other clinical characteristics, including medication use, were unknown.

However, it’s presumed that most patients had TRD, because insurance reimbursement for TMS typically requires an extensive history of failed antidepressant treatment.

Commenting on the study for an interview, Mark George, MD, professor, and Layton McCurdy, endowed chair in psychiatry, the Medical University of South Carolina, Charleston, called the remission and response rates “remarkable.”

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

Treatment with transcranial magnetic stimulation (TMS) has a robust effect for patients with major depressive disorder (MDD), results from a large registry study show.

From patient self-reports and clinician assessments, investigators found that TMS was “surprisingly effective” and “an eye-opener” for these patients, lead investigator Harold A. Sackeim, PhD, professor of clinical psychology in psychiatry and radiology, Columbia University, New York, told this news organization.

“In a presumably treatment-resistant population, the efficacy compared favorably with virtually all pharmacologic treatments” tested in the studies, said Dr. Sackeim.

He noted that the registry from which the data were obtained “is the largest for any treatment of depression, period.” These positive results suggest TMS should be considered a first-line treatment for MDD, he added.

The study was presented at the virtual American Psychiatric Association 2021 Annual Meeting and was previously published in the Journal of Affective Disorders.
 

Real-world study

Results of randomized clinical trials have shown that TMS is effective for episodes of MDD. However, the investigators note that there is a need to characterize and identify patient- and treatment-related clinical outcomes.

The study included 5,010 adult patients who had received a primary diagnosis of MDD and were treated at 103 practices in the United States. Participants completed the nine-item Patient Health Questionnaire (PHQ-9) at baseline and at least one other time following a TMS treatment.

The average baseline PHQ-9 score was 19.8, indicating moderate to severe symptoms. This was also reflected in a smaller sample that included Clinical Global Impressions–Severity (CGI-S) ratings by clinicians, mostly psychiatrists.

About two-thirds of the study population were women. The average age was about 50 years. Participants typically received about 30 TMS sessions over 7 to 8 weeks.

TMS targets tissue in the dorsolateral prefrontal cortex. The standard protocol involves administering “fast” or high-frequency (10-Hz) stimulation on the left side. Sometimes, slow-frequency stimulation on the right side is added. About 57% of patients were treated on the left side, and 43% were treated on both sides. Each session involved delivery of about 3,000 pulses.

In the analysis of patient self-reports (PHQ-9), the response rate, which was defined as resolution of 50% or more of symptoms, was from 58% to 69%. The remission rate, defined as becoming asymptomatic or having minimal symptoms, ranged from 28% to 36%.

Results were about 5% higher in the “completer” sample, which included 3,814 patients who received at least 20 treatments and who completed a PHQ-9 assessment at the end the treatment course.

The number of completers in the analysis was “massive,” said Dr. Sackeim. It’s “ten times larger than in any previous TMS study; all randomized trials have a couple of hundred subjects at most, so this is whopping.”

The results provide “a full snapshot” of TMS in the “real-world” community instead of in the “highly controlled” environment of most studies, he added.
 

Gender differences

The analysis that included CGI-S clinician measures yielded higher outcome estimates – 79% to 83% for the response rate, and 47% to 63% for the remission rate.

Women tended to have better clinical outcomes. “It appears to me that around age 50 is where you see the difference,” said Dr. Sackeim. “Among women, it looks like the older they get, the better the outcome, whereas men are not showing that type of positive aging effect.”

This difference might be due to hormonal changes associated with menopause and the fact that older men with depression may have had a stroke or brain lesion. Dr. Sackeim said he plans to look more closely at outcomes of women in comparison with men.

The finding of a significant positive effect on aging contrasts with earlier research suggesting that age was a negative predictor. This, said Dr. Sackeim, illustrates how rapidly the TMS field is evolving.

He noted that researchers are now personalizing the procedure by determining the optimal target for individual patients. Other investigators are testing different protocols.

In the current study, results tended to be better for those who received 4,000 or more pulses, said Dr. Sackeim. “There was an indication of a dose response effect in terms of how many pulses per session,” he said.

The authors note that the study’s PDQ-9 response and remission rates indicate that clinical outcomes are comparable to those of the seven antidepressants studied in Level 2 of the large Sequenced Treatment Alternatives to Relieve Depression (STAR-D) trial.

Initial data for relapse in the study population are “encouraging,” said Dr. Sackeim. “You don’t see the rapid relapse that you do when you discontinue some treatments, for example with ECT [electroconvulsive therapy].”

The “slower onset of action” over the course of several sessions “may induce longer benefit,” he added.
 

Expanded use warranted?

The intervention proved very safe. Side effects, including headaches, were minimal, and there were “virtually no cognitive effects,” said Dr. Sackeim.

Dr. Sackeim believes TMS, as it has evolved, “is an outstanding option for treatment-resistant depression, and it has a very bright future” and should not be reserved for patients with established treatment-resistant depression (TRD), which is the current U.S. Food and Drug Administration indication.

“Restricting it to TRD in my mind is probably a mistake. Why shouldn’t the patient who is just starting on their course of treatment for depression have this as a nonpharmacological option?” he said.

Limitations of the study included its open-label design and the fact that only patients’ age, gender, outcome scores, and TMS treatment parameters were recorded in the registry. Other clinical characteristics, including medication use, were unknown.

However, it’s presumed that most patients had TRD, because insurance reimbursement for TMS typically requires an extensive history of failed antidepressant treatment.

Commenting on the study for an interview, Mark George, MD, professor, and Layton McCurdy, endowed chair in psychiatry, the Medical University of South Carolina, Charleston, called the remission and response rates “remarkable.”

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

Treatment with transcranial magnetic stimulation (TMS) has a robust effect for patients with major depressive disorder (MDD), results from a large registry study show.

From patient self-reports and clinician assessments, investigators found that TMS was “surprisingly effective” and “an eye-opener” for these patients, lead investigator Harold A. Sackeim, PhD, professor of clinical psychology in psychiatry and radiology, Columbia University, New York, told this news organization.

“In a presumably treatment-resistant population, the efficacy compared favorably with virtually all pharmacologic treatments” tested in the studies, said Dr. Sackeim.

He noted that the registry from which the data were obtained “is the largest for any treatment of depression, period.” These positive results suggest TMS should be considered a first-line treatment for MDD, he added.

The study was presented at the virtual American Psychiatric Association 2021 Annual Meeting and was previously published in the Journal of Affective Disorders.
 

Real-world study

Results of randomized clinical trials have shown that TMS is effective for episodes of MDD. However, the investigators note that there is a need to characterize and identify patient- and treatment-related clinical outcomes.

The study included 5,010 adult patients who had received a primary diagnosis of MDD and were treated at 103 practices in the United States. Participants completed the nine-item Patient Health Questionnaire (PHQ-9) at baseline and at least one other time following a TMS treatment.

The average baseline PHQ-9 score was 19.8, indicating moderate to severe symptoms. This was also reflected in a smaller sample that included Clinical Global Impressions–Severity (CGI-S) ratings by clinicians, mostly psychiatrists.

About two-thirds of the study population were women. The average age was about 50 years. Participants typically received about 30 TMS sessions over 7 to 8 weeks.

TMS targets tissue in the dorsolateral prefrontal cortex. The standard protocol involves administering “fast” or high-frequency (10-Hz) stimulation on the left side. Sometimes, slow-frequency stimulation on the right side is added. About 57% of patients were treated on the left side, and 43% were treated on both sides. Each session involved delivery of about 3,000 pulses.

In the analysis of patient self-reports (PHQ-9), the response rate, which was defined as resolution of 50% or more of symptoms, was from 58% to 69%. The remission rate, defined as becoming asymptomatic or having minimal symptoms, ranged from 28% to 36%.

Results were about 5% higher in the “completer” sample, which included 3,814 patients who received at least 20 treatments and who completed a PHQ-9 assessment at the end the treatment course.

The number of completers in the analysis was “massive,” said Dr. Sackeim. It’s “ten times larger than in any previous TMS study; all randomized trials have a couple of hundred subjects at most, so this is whopping.”

The results provide “a full snapshot” of TMS in the “real-world” community instead of in the “highly controlled” environment of most studies, he added.
 

Gender differences

The analysis that included CGI-S clinician measures yielded higher outcome estimates – 79% to 83% for the response rate, and 47% to 63% for the remission rate.

Women tended to have better clinical outcomes. “It appears to me that around age 50 is where you see the difference,” said Dr. Sackeim. “Among women, it looks like the older they get, the better the outcome, whereas men are not showing that type of positive aging effect.”

This difference might be due to hormonal changes associated with menopause and the fact that older men with depression may have had a stroke or brain lesion. Dr. Sackeim said he plans to look more closely at outcomes of women in comparison with men.

The finding of a significant positive effect on aging contrasts with earlier research suggesting that age was a negative predictor. This, said Dr. Sackeim, illustrates how rapidly the TMS field is evolving.

He noted that researchers are now personalizing the procedure by determining the optimal target for individual patients. Other investigators are testing different protocols.

In the current study, results tended to be better for those who received 4,000 or more pulses, said Dr. Sackeim. “There was an indication of a dose response effect in terms of how many pulses per session,” he said.

The authors note that the study’s PDQ-9 response and remission rates indicate that clinical outcomes are comparable to those of the seven antidepressants studied in Level 2 of the large Sequenced Treatment Alternatives to Relieve Depression (STAR-D) trial.

Initial data for relapse in the study population are “encouraging,” said Dr. Sackeim. “You don’t see the rapid relapse that you do when you discontinue some treatments, for example with ECT [electroconvulsive therapy].”

The “slower onset of action” over the course of several sessions “may induce longer benefit,” he added.
 

Expanded use warranted?

The intervention proved very safe. Side effects, including headaches, were minimal, and there were “virtually no cognitive effects,” said Dr. Sackeim.

Dr. Sackeim believes TMS, as it has evolved, “is an outstanding option for treatment-resistant depression, and it has a very bright future” and should not be reserved for patients with established treatment-resistant depression (TRD), which is the current U.S. Food and Drug Administration indication.

“Restricting it to TRD in my mind is probably a mistake. Why shouldn’t the patient who is just starting on their course of treatment for depression have this as a nonpharmacological option?” he said.

Limitations of the study included its open-label design and the fact that only patients’ age, gender, outcome scores, and TMS treatment parameters were recorded in the registry. Other clinical characteristics, including medication use, were unknown.

However, it’s presumed that most patients had TRD, because insurance reimbursement for TMS typically requires an extensive history of failed antidepressant treatment.

Commenting on the study for an interview, Mark George, MD, professor, and Layton McCurdy, endowed chair in psychiatry, the Medical University of South Carolina, Charleston, called the remission and response rates “remarkable.”

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

Ambulatory care utilization fell to below expected levels during the pandemic, according to an analysis of national claims data from Jan. 1, 2019, to Oct. 31, 2020.

“The COVID-19 pandemic has seriously disrupted access to U.S. ambulatory care, endangering population health,” said John N. Mafi, MD, of the University of California, Los Angeles, in a presentation at the annual meeting of the Society of General Internal Medicine.

Dr. Mafi and colleagues conducted the analysis, which included 20 monthly cohorts, and measured outpatient visit rates per 100 members across all 20 study months. The researchers used a “difference-in-differences study design” and compared changes in rates of ambulatory care visits in January-February 2019 through September-October 2019 with the same periods in 2020.

They found that overall utilization fell to 68.9% of expected rates. This number increased to 82.6% of expected rates by May-June 2020 and to 87.7% of expected rates by July-August 2020.

To examine the impact of COVID-19 on U.S. ambulatory care patterns, the researchers identified 10.4 million individuals aged 18 years and older using the MedInsight research claims database. This database included Medicaid, commercial, dual eligible (receiving both Medicare and Medicaid benefits), Medicare Advantage (MA), and Medicare fee-for-service (FFS) patients. The average age of the individuals studied was 52 years, and 55% of the population were women. The researchers measured outpatient visit rates per 100 beneficiaries for several types of ambulatory care visits: emergency, urgent care, office, physical exams, preventive, alcohol/drug, and psychiatric care.

The researchers verified parallel trends in visits between 2018 and 2019 to establish a historical benchmark and divided the patient population into three groups based on insurance enrollment (continuously enrolled, not continuously enrolled, and fully enrolled) to account for new members adding insurance and disrupted coverage caused by job losses or other factors. The trends in ambulatory care utilization were similar between cohorts across the groups.

The rebound seen by the summer of 2020 showed variation when broken out by insurance type: 94.0% for Medicare FFS; 88.9% for commercial insurance; 86.3% for Medicare Advantage; 83.6% for dual eligible; and 78.0% for Medicaid.

“The big picture is that utilization looks similar across the three groups and has not attained prepandemic levels,” Dr. Mafi said.

When the results were divided by service type, utilization rates remained below expected rates while needs remain similar for U.S. Preventive Services Task Force–recommended preventive screening services, Dr. Mafi noted. The demand for psychiatric and substance use services has increased, but use rates are below expected rates. In addition, both avoidable and nonavoidable ED utilization both remained below expected rates.

In-person visits are down across insurance groups, but virtual visits are skyrocketing, across all insurance groups, Dr. Mafi added. However, virtual care visits have not completely compensated for declines in in-person visits, notably among dual-eligible and Medicaid insurance members.

Takeaways for policy makers include the fact that, while some reductions in unnecessary care, such as avoidable ED visits, may be beneficial, the “reduced USPSTF-recommended cancer and other evidence-based disease prevention may worsen health outcomes, particularly for Medicaid beneficiaries,” he said.
 

Outreach and outcomes

The study is important because “understanding ambulatory care patterns during the pandemic can highlight vulnerabilities and opportunities in our health care system,” Dr. Mafi said in an interview.

“While the COVID-19 pandemic has seriously disrupted access to U.S. ambulatory care, most studies have focused on the early months of the pandemic,” he noted.  

Dr. Mafi said he was not surprised that ambulatory care utilization has not rebounded among Medicaid beneficiaries relative to other insurance groups.

“Medicaid beneficiaries are underresourced individuals who are disproportionately racial/ethnic minorities, and they historically have had difficulties accessing care. Our data suggest that the COVID-19 pandemic may be widening these preexisting inequities in access to ambulatory care,” he observed.

The study findings were limited by the use of the MedInsight research dataset, which is a convenience sample; and, therefore, the results might not be generalizable nationally, Dr. Mafi said. “However, it does include beneficiaries from all major insurance types across all 50 U.S. states. Additionally, our analysis was completed at the population level rather than the patient level, and so we were unable to account for patient-level characteristics such as clinical complexity,” he explained.

“The take-home message for clinicians is that our patients with Medicaid insurance may need additional efforts to overcome barriers to accessing ambulatory care, such as creating robust telemedicine outreach programs,” said Dr. Mafi. “Policy makers should also consider providing additional support and resources to safety net health systems who disproportionately care for Medicaid beneficiaries, such as higher reimbursements for both in-person and telemedicine visits.”

More research is needed, he emphasized. “We urgently need further inquiry into the impact of this persistently deferred ambulatory care utilization on important health outcomes such as preventable death/disability and quality of care.”
 

COVID consequences challenge ambulatory care

“These study findings mirror what we are seeing in primary care settings,” Maureen Lyons, MD, of Washington University. St. Louis, said in an interview. “With the pandemic, there are many additional barriers for patients accessing care, and these barriers have disproportionately impacted those who are already disadvantaged.

“From clinical experience, there are barriers directly related to COVID-19, such as the risk of infection or discomfort being in a clinic setting with other people. However, there also are barriers related to change in financial situation or insurance related to changes or loss of employment,” she said.

“Additionally, many patients have needed to take on increased responsibilities in other areas of their lives, such as caring for an ill family member or being responsible for children’s virtual school,” she said. These new responsibilities can lead people to skip or postpone ambulatory care visits.

“Loss of ambulatory care is likely to lead to increases in preventable illnesses with long-lasting effects,” Dr. Lyons noted. “Studying this in a robust fashion, as Dr. Mafi and colleagues have done, is a critical step in understanding and addressing this urgent need.”

Dr. Mafi noted that the data he presented is preliminary, and that he and his team hope to publish finalized estimates of ambulatory utilization rates in a forthcoming scientific paper.

The study was a collaboration between UCLA and Millman MedInsight, an actuarial health analytics company. Several coauthors are Millman employees. Dr. Mafi and the other researchers had no other relevant financial conflicts to disclose. Dr. Lyons had no financial conflicts to disclose.

Ambulatory care utilization fell to below expected levels during the pandemic, according to an analysis of national claims data from Jan. 1, 2019, to Oct. 31, 2020.

“The COVID-19 pandemic has seriously disrupted access to U.S. ambulatory care, endangering population health,” said John N. Mafi, MD, of the University of California, Los Angeles, in a presentation at the annual meeting of the Society of General Internal Medicine.

Dr. Mafi and colleagues conducted the analysis, which included 20 monthly cohorts, and measured outpatient visit rates per 100 members across all 20 study months. The researchers used a “difference-in-differences study design” and compared changes in rates of ambulatory care visits in January-February 2019 through September-October 2019 with the same periods in 2020.

They found that overall utilization fell to 68.9% of expected rates. This number increased to 82.6% of expected rates by May-June 2020 and to 87.7% of expected rates by July-August 2020.

To examine the impact of COVID-19 on U.S. ambulatory care patterns, the researchers identified 10.4 million individuals aged 18 years and older using the MedInsight research claims database. This database included Medicaid, commercial, dual eligible (receiving both Medicare and Medicaid benefits), Medicare Advantage (MA), and Medicare fee-for-service (FFS) patients. The average age of the individuals studied was 52 years, and 55% of the population were women. The researchers measured outpatient visit rates per 100 beneficiaries for several types of ambulatory care visits: emergency, urgent care, office, physical exams, preventive, alcohol/drug, and psychiatric care.

The researchers verified parallel trends in visits between 2018 and 2019 to establish a historical benchmark and divided the patient population into three groups based on insurance enrollment (continuously enrolled, not continuously enrolled, and fully enrolled) to account for new members adding insurance and disrupted coverage caused by job losses or other factors. The trends in ambulatory care utilization were similar between cohorts across the groups.

The rebound seen by the summer of 2020 showed variation when broken out by insurance type: 94.0% for Medicare FFS; 88.9% for commercial insurance; 86.3% for Medicare Advantage; 83.6% for dual eligible; and 78.0% for Medicaid.

“The big picture is that utilization looks similar across the three groups and has not attained prepandemic levels,” Dr. Mafi said.

When the results were divided by service type, utilization rates remained below expected rates while needs remain similar for U.S. Preventive Services Task Force–recommended preventive screening services, Dr. Mafi noted. The demand for psychiatric and substance use services has increased, but use rates are below expected rates. In addition, both avoidable and nonavoidable ED utilization both remained below expected rates.

In-person visits are down across insurance groups, but virtual visits are skyrocketing, across all insurance groups, Dr. Mafi added. However, virtual care visits have not completely compensated for declines in in-person visits, notably among dual-eligible and Medicaid insurance members.

Takeaways for policy makers include the fact that, while some reductions in unnecessary care, such as avoidable ED visits, may be beneficial, the “reduced USPSTF-recommended cancer and other evidence-based disease prevention may worsen health outcomes, particularly for Medicaid beneficiaries,” he said.
 

Outreach and outcomes

The study is important because “understanding ambulatory care patterns during the pandemic can highlight vulnerabilities and opportunities in our health care system,” Dr. Mafi said in an interview.

“While the COVID-19 pandemic has seriously disrupted access to U.S. ambulatory care, most studies have focused on the early months of the pandemic,” he noted.  

Dr. Mafi said he was not surprised that ambulatory care utilization has not rebounded among Medicaid beneficiaries relative to other insurance groups.

“Medicaid beneficiaries are underresourced individuals who are disproportionately racial/ethnic minorities, and they historically have had difficulties accessing care. Our data suggest that the COVID-19 pandemic may be widening these preexisting inequities in access to ambulatory care,” he observed.

The study findings were limited by the use of the MedInsight research dataset, which is a convenience sample; and, therefore, the results might not be generalizable nationally, Dr. Mafi said. “However, it does include beneficiaries from all major insurance types across all 50 U.S. states. Additionally, our analysis was completed at the population level rather than the patient level, and so we were unable to account for patient-level characteristics such as clinical complexity,” he explained.

“The take-home message for clinicians is that our patients with Medicaid insurance may need additional efforts to overcome barriers to accessing ambulatory care, such as creating robust telemedicine outreach programs,” said Dr. Mafi. “Policy makers should also consider providing additional support and resources to safety net health systems who disproportionately care for Medicaid beneficiaries, such as higher reimbursements for both in-person and telemedicine visits.”

More research is needed, he emphasized. “We urgently need further inquiry into the impact of this persistently deferred ambulatory care utilization on important health outcomes such as preventable death/disability and quality of care.”
 

COVID consequences challenge ambulatory care

“These study findings mirror what we are seeing in primary care settings,” Maureen Lyons, MD, of Washington University. St. Louis, said in an interview. “With the pandemic, there are many additional barriers for patients accessing care, and these barriers have disproportionately impacted those who are already disadvantaged.

“From clinical experience, there are barriers directly related to COVID-19, such as the risk of infection or discomfort being in a clinic setting with other people. However, there also are barriers related to change in financial situation or insurance related to changes or loss of employment,” she said.

“Additionally, many patients have needed to take on increased responsibilities in other areas of their lives, such as caring for an ill family member or being responsible for children’s virtual school,” she said. These new responsibilities can lead people to skip or postpone ambulatory care visits.

“Loss of ambulatory care is likely to lead to increases in preventable illnesses with long-lasting effects,” Dr. Lyons noted. “Studying this in a robust fashion, as Dr. Mafi and colleagues have done, is a critical step in understanding and addressing this urgent need.”

Dr. Mafi noted that the data he presented is preliminary, and that he and his team hope to publish finalized estimates of ambulatory utilization rates in a forthcoming scientific paper.

The study was a collaboration between UCLA and Millman MedInsight, an actuarial health analytics company. Several coauthors are Millman employees. Dr. Mafi and the other researchers had no other relevant financial conflicts to disclose. Dr. Lyons had no financial conflicts to disclose.

Ambulatory care utilization fell to below expected levels during the pandemic, according to an analysis of national claims data from Jan. 1, 2019, to Oct. 31, 2020.

“The COVID-19 pandemic has seriously disrupted access to U.S. ambulatory care, endangering population health,” said John N. Mafi, MD, of the University of California, Los Angeles, in a presentation at the annual meeting of the Society of General Internal Medicine.

Dr. Mafi and colleagues conducted the analysis, which included 20 monthly cohorts, and measured outpatient visit rates per 100 members across all 20 study months. The researchers used a “difference-in-differences study design” and compared changes in rates of ambulatory care visits in January-February 2019 through September-October 2019 with the same periods in 2020.

They found that overall utilization fell to 68.9% of expected rates. This number increased to 82.6% of expected rates by May-June 2020 and to 87.7% of expected rates by July-August 2020.

To examine the impact of COVID-19 on U.S. ambulatory care patterns, the researchers identified 10.4 million individuals aged 18 years and older using the MedInsight research claims database. This database included Medicaid, commercial, dual eligible (receiving both Medicare and Medicaid benefits), Medicare Advantage (MA), and Medicare fee-for-service (FFS) patients. The average age of the individuals studied was 52 years, and 55% of the population were women. The researchers measured outpatient visit rates per 100 beneficiaries for several types of ambulatory care visits: emergency, urgent care, office, physical exams, preventive, alcohol/drug, and psychiatric care.

The researchers verified parallel trends in visits between 2018 and 2019 to establish a historical benchmark and divided the patient population into three groups based on insurance enrollment (continuously enrolled, not continuously enrolled, and fully enrolled) to account for new members adding insurance and disrupted coverage caused by job losses or other factors. The trends in ambulatory care utilization were similar between cohorts across the groups.

The rebound seen by the summer of 2020 showed variation when broken out by insurance type: 94.0% for Medicare FFS; 88.9% for commercial insurance; 86.3% for Medicare Advantage; 83.6% for dual eligible; and 78.0% for Medicaid.

“The big picture is that utilization looks similar across the three groups and has not attained prepandemic levels,” Dr. Mafi said.

When the results were divided by service type, utilization rates remained below expected rates while needs remain similar for U.S. Preventive Services Task Force–recommended preventive screening services, Dr. Mafi noted. The demand for psychiatric and substance use services has increased, but use rates are below expected rates. In addition, both avoidable and nonavoidable ED utilization both remained below expected rates.

In-person visits are down across insurance groups, but virtual visits are skyrocketing, across all insurance groups, Dr. Mafi added. However, virtual care visits have not completely compensated for declines in in-person visits, notably among dual-eligible and Medicaid insurance members.

Takeaways for policy makers include the fact that, while some reductions in unnecessary care, such as avoidable ED visits, may be beneficial, the “reduced USPSTF-recommended cancer and other evidence-based disease prevention may worsen health outcomes, particularly for Medicaid beneficiaries,” he said.
 

Outreach and outcomes

The study is important because “understanding ambulatory care patterns during the pandemic can highlight vulnerabilities and opportunities in our health care system,” Dr. Mafi said in an interview.

“While the COVID-19 pandemic has seriously disrupted access to U.S. ambulatory care, most studies have focused on the early months of the pandemic,” he noted.  

Dr. Mafi said he was not surprised that ambulatory care utilization has not rebounded among Medicaid beneficiaries relative to other insurance groups.

“Medicaid beneficiaries are underresourced individuals who are disproportionately racial/ethnic minorities, and they historically have had difficulties accessing care. Our data suggest that the COVID-19 pandemic may be widening these preexisting inequities in access to ambulatory care,” he observed.

The study findings were limited by the use of the MedInsight research dataset, which is a convenience sample; and, therefore, the results might not be generalizable nationally, Dr. Mafi said. “However, it does include beneficiaries from all major insurance types across all 50 U.S. states. Additionally, our analysis was completed at the population level rather than the patient level, and so we were unable to account for patient-level characteristics such as clinical complexity,” he explained.

“The take-home message for clinicians is that our patients with Medicaid insurance may need additional efforts to overcome barriers to accessing ambulatory care, such as creating robust telemedicine outreach programs,” said Dr. Mafi. “Policy makers should also consider providing additional support and resources to safety net health systems who disproportionately care for Medicaid beneficiaries, such as higher reimbursements for both in-person and telemedicine visits.”

More research is needed, he emphasized. “We urgently need further inquiry into the impact of this persistently deferred ambulatory care utilization on important health outcomes such as preventable death/disability and quality of care.”
 

COVID consequences challenge ambulatory care

“These study findings mirror what we are seeing in primary care settings,” Maureen Lyons, MD, of Washington University. St. Louis, said in an interview. “With the pandemic, there are many additional barriers for patients accessing care, and these barriers have disproportionately impacted those who are already disadvantaged.

“From clinical experience, there are barriers directly related to COVID-19, such as the risk of infection or discomfort being in a clinic setting with other people. However, there also are barriers related to change in financial situation or insurance related to changes or loss of employment,” she said.

“Additionally, many patients have needed to take on increased responsibilities in other areas of their lives, such as caring for an ill family member or being responsible for children’s virtual school,” she said. These new responsibilities can lead people to skip or postpone ambulatory care visits.

“Loss of ambulatory care is likely to lead to increases in preventable illnesses with long-lasting effects,” Dr. Lyons noted. “Studying this in a robust fashion, as Dr. Mafi and colleagues have done, is a critical step in understanding and addressing this urgent need.”

Dr. Mafi noted that the data he presented is preliminary, and that he and his team hope to publish finalized estimates of ambulatory utilization rates in a forthcoming scientific paper.

The study was a collaboration between UCLA and Millman MedInsight, an actuarial health analytics company. Several coauthors are Millman employees. Dr. Mafi and the other researchers had no other relevant financial conflicts to disclose. Dr. Lyons had no financial conflicts to disclose.

A novel physical rehabilitation program for patients with advanced heart failure that aimed to improve their ability to exercise before focusing on endurance was successful in a randomized trial in ways that seem to have eluded some earlier exercise-training studies in the setting of HF.

The often-frail patients following the training regimen, initiated before discharge from hospitalization for acute decompensation, worked on capabilities such as mobility, balance, and strength deemed necessary if exercises meant to build exercise capacity were to succeed.

A huge percentage stayed with the 12-week program, which featured personalized, one-on-one training from a physical therapist. The patients benefited, with improvements in balance, walking ability, and strength, which were followed by significant gains in 6-minute walk distance (6MWD) and measures of physical functioning, frailty, and quality of life. The patients then continued elements of the program at home out to 6 months.

At that time, death and rehospitalizations did not differ between those assigned to the regimen and similar patients who had not participated in the program, although the trial wasn’t powered for clinical events.

The rehab strategy seemed to work across a wide range of patient subgroups. In particular, there was evidence that the benefits were more pronounced in patients with HF and preserved ejection fraction (HFpEF) than in those with HF and reduced ejection fraction (HFrEF), observed Dalane W. Kitzman, MD, Wake Forest University, Winston-Salem, N.C.

Dr. Kitzman presented results from the REHAB-HF (Rehabilitation Therapy in Older Acute Heart Failure Patients) trial at the annual scientific sessions of the American College of Cardiology and is lead author on its same-day publication in the New England Journal of Medicine.

An earlier pilot program unexpectedly showed that such patients recently hospitalized with HF “have significant impairments in mobility and balance,” he explained. If so, “it would be hazardous to subject them to traditional endurance training, such as walking-based treadmill or even bicycle.”

The unusual program, said Dr. Kitzman, looks to those issues before engaging the patients in endurance exercise by addressing mobility, balance, and basic strength – enough to repeatedly stand up from a sitting position, for example. “If you’re not able to stand with confidence, then you’re not able to walk on a treadmill.”

This model of exercise rehab “is used in geriatrics research, and enables them to safely increase endurance. It’s well known from geriatric studies that if you go directly to endurance in these, frail, older patients, you have little improvement and often have injuries and falls,” he added.
 

Guidance from telemedicine?

The functional outcomes examined in REHAB-HF “are the ones that matter to patients the most,” observed Eileen M. Handberg, PhD, of Shands Hospital at the University of Florida, Gainesville, at a presentation on the trial for the media.

“This is about being able to get out of a chair without assistance, not falling, walking farther, and feeling better as opposed to the more traditional outcome measure that has been used in cardiac rehab trials, which has been the exercise treadmill test – which most patients don’t have the capacity to do very well anyway,” said Dr. Handberg, who is not a part of REHAB-HF.

“This opens up rehab, potentially, to the more sick, who also need a better quality of life,” she said.

However, many patients invited to participate in the trial could not because they lived too far from the program, Dr. Handberg observed. “It would be nice to see if the lessons from COVID-19 might apply to this population” by making participation possible remotely, “perhaps using family members as rehab assistance,” she said.

“I was really very impressed that you had 83% adherence to a home exercise 6 months down the road, which far eclipses what we had in HF-ACTION,” said Vera Bittner, MD, University of Alabama at Birmingham, as the invited discussant following Dr. Kitzman’s formal presentation of the trial. “And it certainly eclipses what we see in the typical cardiac rehab program.”

Both Dr. Bittner and Dr. Kitzman participated in HF-ACTION, a randomized exercise-training trial for patients with chronic, stable HFrEF who were all-around less sick than those in REHAB-HF.
 

Four functional domains

Historically, HF exercise or rehab trials have excluded patients hospitalized with acute decompensation, and third-party reimbursement often has not covered such programs because of a lack of supporting evidence and a supposed potential for harm, Dr. Kitzman said.

Entry to REHAB-HF required the patients to be fit enough to walk 4 meters, with or without a walker or other assistant device, and to have been in the hospital for at least 24 hours with a primary diagnosis of acute decompensated HF.

The intervention relied on exercises aimed at improving the four functional domains of strength, balance, mobility, and – when those three were sufficiently developed – endurance, Dr. Kitzman and associates wrote in their published report.

“The intervention was initiated in the hospital when feasible and was subsequently transitioned to an outpatient facility as soon as possible after discharge,” they wrote. Afterward, “a key goal of the intervention during the first 3 months [the outpatient phase] was to prepare the patient to transition to the independent maintenance phase (months 4-6).”

The study’s control patients “received frequent calls from study staff to try to approximate the increased attention received by the intervention group,” Dr. Kitzman said in an interview. “They were allowed to receive all usual care as ordered by their treating physicians. This included, if ordered, standard physical therapy or cardiac rehabilitation” in 43% of the control cohort. Of the trial’s 349 patients, those assigned to the intervention scored significantly higher on the three-component Short Physical Performance Battery (SPPB) at 12 weeks than those assigned to a usual care approach that included, for some, more conventional cardiac rehabilitation (8.3 vs. 6.9; P < .001).

The SPPB, validated in trials as a proxy for clinical outcomes includes tests of balance while standing, gait speed during a 4-minute walk, and strength. The latter is the test that measures time needed to rise from a chair five times.

They also showed consistent gains in other measures of physical functioning and quality of life by 12 weeks months.

The observed SPPB treatment effect is “impressive” and “compares very favorably with previously reported estimates,” observed an accompanying editorial from Stefan D. Anker, MD, PhD, of the German Center for Cardiovascular Research and Charité Universitätsmedizin, Berlin, and Andrew J.S. Coats, DM, of the University of Warwick, Coventry, England.

“Similarly, the between-group differences seen in 6-minute walk distance (34 m) and gait speed (0.12 m/s) are clinically meaningful and sizable.”

They propose that some of the substantial quality-of-life benefit in the intervention group “may be due to better physical performance, and that part may be due to improvements in psychosocial factors and mood. It appears that exercise also resulted in patients becoming happier, or at least less depressed, as evidenced by the positive results on the Geriatric Depression Scale.”
 

Similar results across most subgroups

In subgroup analyses, the intervention was successful against the standard-care approach in both men and women at all ages and regardless of ejection fraction; symptom status; and whether the patient had diabetes, ischemic heart disease, or atrial fibrillation, or was obese.

Clinical outcomes were not significantly different at 6 months. The rate of death from any cause was 13% for the intervention group and 10% for the control group. There were 194 and 213 hospitalizations from any cause, respectively.

Not included in the trial’s current publication but soon to be published, Dr. Kitzman said when interviewed, is a comparison of outcomes in patients with HFpEF and HFrEF. “We found at baseline that those with HFpEF had worse impairment in physical function, quality of life, and frailty. After the intervention, there appeared to be consistently larger improvements in all outcomes, including SPPB, 6-minute walk, qualify of life, and frailty, in HFpEF versus HFrEF.”

The signals of potential benefit in HFpEF extended to clinical endpoints, he said. In contrast to similar rates of all-cause rehospitalization in HFrEF, “in patients with HFpEF, rehospitalizations were 17% lower in the intervention group, compared to the control group.” Still, he noted, the interaction P value wasn’t significant.

However, Dr. Kitzman added, mortality in the intervention group, compared with the control group, was reduced by 35% among patients with HFpEF, “but was 250% higher in HFrEF,” with a significant interaction P value.

He was careful to note that, as a phase 2 trial, REHAB-HF was underpowered for clinical events, “and even the results in the HFpEF group should not be seen as adequate evidence to change clinical care.” They were from an exploratory analysis that included relatively few events.

“Because definitive demonstration of improvement in clinical events is critical for altering clinical care guidelines and for third-party payer reimbursement decisions, we believe that a subsequent phase 3 trial is needed and are currently planning toward that,” Dr. Kitzman said.

The study was supported by research grants from the National Institutes of Health, the Kermit Glenn Phillips II Chair in Cardiovascular Medicine, and the Oristano Family Fund at Wake Forest. Dr. Kitzman disclosed receiving consulting fees or honoraria from AbbVie, AstraZeneca, Bayer Healthcare, Boehringer Ingelheim, CinRx, Corviamedical, GlaxoSmithKline, and Merck; and having an unspecified relationship with Gilead. Dr. Handberg disclosed receiving grants from Aastom Biosciences, Abbott Laboratories, Amgen, Amorcyte, AstraZeneca, Biocardia, Boehringer Ingelheim, Capricor, Cytori Therapeutics, Department of Defense, Direct Flow Medical, Everyfit, Gilead, Ionis, Medtronic, Merck, Mesoblast, Relypsa, and Sanofi-Aventis. Dr. Bittner discloses receiving consulting fees or honoraria from Pfizer and Sanofi; receiving research grants from Amgen and The Medicines Company; and having unspecified relationships with AstraZeneca, DalCor, Esperion, and Sanofi-Aventis. Dr. Anker reported receiving grants and personal fees from Abbott Vascular and Vifor; personal fees from Bayer, Boehringer Ingelheim, Novartis, Servier, Cardiac Dimensions, Thermo Fisher Scientific, AstraZeneca, Occlutech, Actimed, and Respicardia. Dr. Coats disclosed receiving personal fees from AstraZeneca, Bayer, Boehringer Ingelheim, Menarini, Novartis, Nutricia, Servier, Vifor, Abbott, Actimed, Arena, Cardiac Dimensions, Corvia, CVRx, Enopace, ESN Cleer, Faraday, WL Gore, Impulse Dynamics, and Respicardia.

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

A novel physical rehabilitation program for patients with advanced heart failure that aimed to improve their ability to exercise before focusing on endurance was successful in a randomized trial in ways that seem to have eluded some earlier exercise-training studies in the setting of HF.

The often-frail patients following the training regimen, initiated before discharge from hospitalization for acute decompensation, worked on capabilities such as mobility, balance, and strength deemed necessary if exercises meant to build exercise capacity were to succeed.

A huge percentage stayed with the 12-week program, which featured personalized, one-on-one training from a physical therapist. The patients benefited, with improvements in balance, walking ability, and strength, which were followed by significant gains in 6-minute walk distance (6MWD) and measures of physical functioning, frailty, and quality of life. The patients then continued elements of the program at home out to 6 months.

At that time, death and rehospitalizations did not differ between those assigned to the regimen and similar patients who had not participated in the program, although the trial wasn’t powered for clinical events.

The rehab strategy seemed to work across a wide range of patient subgroups. In particular, there was evidence that the benefits were more pronounced in patients with HF and preserved ejection fraction (HFpEF) than in those with HF and reduced ejection fraction (HFrEF), observed Dalane W. Kitzman, MD, Wake Forest University, Winston-Salem, N.C.

Dr. Kitzman presented results from the REHAB-HF (Rehabilitation Therapy in Older Acute Heart Failure Patients) trial at the annual scientific sessions of the American College of Cardiology and is lead author on its same-day publication in the New England Journal of Medicine.

An earlier pilot program unexpectedly showed that such patients recently hospitalized with HF “have significant impairments in mobility and balance,” he explained. If so, “it would be hazardous to subject them to traditional endurance training, such as walking-based treadmill or even bicycle.”

The unusual program, said Dr. Kitzman, looks to those issues before engaging the patients in endurance exercise by addressing mobility, balance, and basic strength – enough to repeatedly stand up from a sitting position, for example. “If you’re not able to stand with confidence, then you’re not able to walk on a treadmill.”

This model of exercise rehab “is used in geriatrics research, and enables them to safely increase endurance. It’s well known from geriatric studies that if you go directly to endurance in these, frail, older patients, you have little improvement and often have injuries and falls,” he added.
 

Guidance from telemedicine?

The functional outcomes examined in REHAB-HF “are the ones that matter to patients the most,” observed Eileen M. Handberg, PhD, of Shands Hospital at the University of Florida, Gainesville, at a presentation on the trial for the media.

“This is about being able to get out of a chair without assistance, not falling, walking farther, and feeling better as opposed to the more traditional outcome measure that has been used in cardiac rehab trials, which has been the exercise treadmill test – which most patients don’t have the capacity to do very well anyway,” said Dr. Handberg, who is not a part of REHAB-HF.

“This opens up rehab, potentially, to the more sick, who also need a better quality of life,” she said.

However, many patients invited to participate in the trial could not because they lived too far from the program, Dr. Handberg observed. “It would be nice to see if the lessons from COVID-19 might apply to this population” by making participation possible remotely, “perhaps using family members as rehab assistance,” she said.

“I was really very impressed that you had 83% adherence to a home exercise 6 months down the road, which far eclipses what we had in HF-ACTION,” said Vera Bittner, MD, University of Alabama at Birmingham, as the invited discussant following Dr. Kitzman’s formal presentation of the trial. “And it certainly eclipses what we see in the typical cardiac rehab program.”

Both Dr. Bittner and Dr. Kitzman participated in HF-ACTION, a randomized exercise-training trial for patients with chronic, stable HFrEF who were all-around less sick than those in REHAB-HF.
 

Four functional domains

Historically, HF exercise or rehab trials have excluded patients hospitalized with acute decompensation, and third-party reimbursement often has not covered such programs because of a lack of supporting evidence and a supposed potential for harm, Dr. Kitzman said.

Entry to REHAB-HF required the patients to be fit enough to walk 4 meters, with or without a walker or other assistant device, and to have been in the hospital for at least 24 hours with a primary diagnosis of acute decompensated HF.

The intervention relied on exercises aimed at improving the four functional domains of strength, balance, mobility, and – when those three were sufficiently developed – endurance, Dr. Kitzman and associates wrote in their published report.

“The intervention was initiated in the hospital when feasible and was subsequently transitioned to an outpatient facility as soon as possible after discharge,” they wrote. Afterward, “a key goal of the intervention during the first 3 months [the outpatient phase] was to prepare the patient to transition to the independent maintenance phase (months 4-6).”

The study’s control patients “received frequent calls from study staff to try to approximate the increased attention received by the intervention group,” Dr. Kitzman said in an interview. “They were allowed to receive all usual care as ordered by their treating physicians. This included, if ordered, standard physical therapy or cardiac rehabilitation” in 43% of the control cohort. Of the trial’s 349 patients, those assigned to the intervention scored significantly higher on the three-component Short Physical Performance Battery (SPPB) at 12 weeks than those assigned to a usual care approach that included, for some, more conventional cardiac rehabilitation (8.3 vs. 6.9; P < .001).

The SPPB, validated in trials as a proxy for clinical outcomes includes tests of balance while standing, gait speed during a 4-minute walk, and strength. The latter is the test that measures time needed to rise from a chair five times.

They also showed consistent gains in other measures of physical functioning and quality of life by 12 weeks months.

The observed SPPB treatment effect is “impressive” and “compares very favorably with previously reported estimates,” observed an accompanying editorial from Stefan D. Anker, MD, PhD, of the German Center for Cardiovascular Research and Charité Universitätsmedizin, Berlin, and Andrew J.S. Coats, DM, of the University of Warwick, Coventry, England.

“Similarly, the between-group differences seen in 6-minute walk distance (34 m) and gait speed (0.12 m/s) are clinically meaningful and sizable.”

They propose that some of the substantial quality-of-life benefit in the intervention group “may be due to better physical performance, and that part may be due to improvements in psychosocial factors and mood. It appears that exercise also resulted in patients becoming happier, or at least less depressed, as evidenced by the positive results on the Geriatric Depression Scale.”
 

Similar results across most subgroups

In subgroup analyses, the intervention was successful against the standard-care approach in both men and women at all ages and regardless of ejection fraction; symptom status; and whether the patient had diabetes, ischemic heart disease, or atrial fibrillation, or was obese.

Clinical outcomes were not significantly different at 6 months. The rate of death from any cause was 13% for the intervention group and 10% for the control group. There were 194 and 213 hospitalizations from any cause, respectively.

Not included in the trial’s current publication but soon to be published, Dr. Kitzman said when interviewed, is a comparison of outcomes in patients with HFpEF and HFrEF. “We found at baseline that those with HFpEF had worse impairment in physical function, quality of life, and frailty. After the intervention, there appeared to be consistently larger improvements in all outcomes, including SPPB, 6-minute walk, qualify of life, and frailty, in HFpEF versus HFrEF.”

The signals of potential benefit in HFpEF extended to clinical endpoints, he said. In contrast to similar rates of all-cause rehospitalization in HFrEF, “in patients with HFpEF, rehospitalizations were 17% lower in the intervention group, compared to the control group.” Still, he noted, the interaction P value wasn’t significant.

However, Dr. Kitzman added, mortality in the intervention group, compared with the control group, was reduced by 35% among patients with HFpEF, “but was 250% higher in HFrEF,” with a significant interaction P value.

He was careful to note that, as a phase 2 trial, REHAB-HF was underpowered for clinical events, “and even the results in the HFpEF group should not be seen as adequate evidence to change clinical care.” They were from an exploratory analysis that included relatively few events.

“Because definitive demonstration of improvement in clinical events is critical for altering clinical care guidelines and for third-party payer reimbursement decisions, we believe that a subsequent phase 3 trial is needed and are currently planning toward that,” Dr. Kitzman said.

The study was supported by research grants from the National Institutes of Health, the Kermit Glenn Phillips II Chair in Cardiovascular Medicine, and the Oristano Family Fund at Wake Forest. Dr. Kitzman disclosed receiving consulting fees or honoraria from AbbVie, AstraZeneca, Bayer Healthcare, Boehringer Ingelheim, CinRx, Corviamedical, GlaxoSmithKline, and Merck; and having an unspecified relationship with Gilead. Dr. Handberg disclosed receiving grants from Aastom Biosciences, Abbott Laboratories, Amgen, Amorcyte, AstraZeneca, Biocardia, Boehringer Ingelheim, Capricor, Cytori Therapeutics, Department of Defense, Direct Flow Medical, Everyfit, Gilead, Ionis, Medtronic, Merck, Mesoblast, Relypsa, and Sanofi-Aventis. Dr. Bittner discloses receiving consulting fees or honoraria from Pfizer and Sanofi; receiving research grants from Amgen and The Medicines Company; and having unspecified relationships with AstraZeneca, DalCor, Esperion, and Sanofi-Aventis. Dr. Anker reported receiving grants and personal fees from Abbott Vascular and Vifor; personal fees from Bayer, Boehringer Ingelheim, Novartis, Servier, Cardiac Dimensions, Thermo Fisher Scientific, AstraZeneca, Occlutech, Actimed, and Respicardia. Dr. Coats disclosed receiving personal fees from AstraZeneca, Bayer, Boehringer Ingelheim, Menarini, Novartis, Nutricia, Servier, Vifor, Abbott, Actimed, Arena, Cardiac Dimensions, Corvia, CVRx, Enopace, ESN Cleer, Faraday, WL Gore, Impulse Dynamics, and Respicardia.

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

A novel physical rehabilitation program for patients with advanced heart failure that aimed to improve their ability to exercise before focusing on endurance was successful in a randomized trial in ways that seem to have eluded some earlier exercise-training studies in the setting of HF.

The often-frail patients following the training regimen, initiated before discharge from hospitalization for acute decompensation, worked on capabilities such as mobility, balance, and strength deemed necessary if exercises meant to build exercise capacity were to succeed.

A huge percentage stayed with the 12-week program, which featured personalized, one-on-one training from a physical therapist. The patients benefited, with improvements in balance, walking ability, and strength, which were followed by significant gains in 6-minute walk distance (6MWD) and measures of physical functioning, frailty, and quality of life. The patients then continued elements of the program at home out to 6 months.

At that time, death and rehospitalizations did not differ between those assigned to the regimen and similar patients who had not participated in the program, although the trial wasn’t powered for clinical events.

The rehab strategy seemed to work across a wide range of patient subgroups. In particular, there was evidence that the benefits were more pronounced in patients with HF and preserved ejection fraction (HFpEF) than in those with HF and reduced ejection fraction (HFrEF), observed Dalane W. Kitzman, MD, Wake Forest University, Winston-Salem, N.C.

Dr. Kitzman presented results from the REHAB-HF (Rehabilitation Therapy in Older Acute Heart Failure Patients) trial at the annual scientific sessions of the American College of Cardiology and is lead author on its same-day publication in the New England Journal of Medicine.

An earlier pilot program unexpectedly showed that such patients recently hospitalized with HF “have significant impairments in mobility and balance,” he explained. If so, “it would be hazardous to subject them to traditional endurance training, such as walking-based treadmill or even bicycle.”

The unusual program, said Dr. Kitzman, looks to those issues before engaging the patients in endurance exercise by addressing mobility, balance, and basic strength – enough to repeatedly stand up from a sitting position, for example. “If you’re not able to stand with confidence, then you’re not able to walk on a treadmill.”

This model of exercise rehab “is used in geriatrics research, and enables them to safely increase endurance. It’s well known from geriatric studies that if you go directly to endurance in these, frail, older patients, you have little improvement and often have injuries and falls,” he added.
 

Guidance from telemedicine?

The functional outcomes examined in REHAB-HF “are the ones that matter to patients the most,” observed Eileen M. Handberg, PhD, of Shands Hospital at the University of Florida, Gainesville, at a presentation on the trial for the media.

“This is about being able to get out of a chair without assistance, not falling, walking farther, and feeling better as opposed to the more traditional outcome measure that has been used in cardiac rehab trials, which has been the exercise treadmill test – which most patients don’t have the capacity to do very well anyway,” said Dr. Handberg, who is not a part of REHAB-HF.

“This opens up rehab, potentially, to the more sick, who also need a better quality of life,” she said.

However, many patients invited to participate in the trial could not because they lived too far from the program, Dr. Handberg observed. “It would be nice to see if the lessons from COVID-19 might apply to this population” by making participation possible remotely, “perhaps using family members as rehab assistance,” she said.

“I was really very impressed that you had 83% adherence to a home exercise 6 months down the road, which far eclipses what we had in HF-ACTION,” said Vera Bittner, MD, University of Alabama at Birmingham, as the invited discussant following Dr. Kitzman’s formal presentation of the trial. “And it certainly eclipses what we see in the typical cardiac rehab program.”

Both Dr. Bittner and Dr. Kitzman participated in HF-ACTION, a randomized exercise-training trial for patients with chronic, stable HFrEF who were all-around less sick than those in REHAB-HF.
 

Four functional domains

Historically, HF exercise or rehab trials have excluded patients hospitalized with acute decompensation, and third-party reimbursement often has not covered such programs because of a lack of supporting evidence and a supposed potential for harm, Dr. Kitzman said.

Entry to REHAB-HF required the patients to be fit enough to walk 4 meters, with or without a walker or other assistant device, and to have been in the hospital for at least 24 hours with a primary diagnosis of acute decompensated HF.

The intervention relied on exercises aimed at improving the four functional domains of strength, balance, mobility, and – when those three were sufficiently developed – endurance, Dr. Kitzman and associates wrote in their published report.

“The intervention was initiated in the hospital when feasible and was subsequently transitioned to an outpatient facility as soon as possible after discharge,” they wrote. Afterward, “a key goal of the intervention during the first 3 months [the outpatient phase] was to prepare the patient to transition to the independent maintenance phase (months 4-6).”

The study’s control patients “received frequent calls from study staff to try to approximate the increased attention received by the intervention group,” Dr. Kitzman said in an interview. “They were allowed to receive all usual care as ordered by their treating physicians. This included, if ordered, standard physical therapy or cardiac rehabilitation” in 43% of the control cohort. Of the trial’s 349 patients, those assigned to the intervention scored significantly higher on the three-component Short Physical Performance Battery (SPPB) at 12 weeks than those assigned to a usual care approach that included, for some, more conventional cardiac rehabilitation (8.3 vs. 6.9; P < .001).

The SPPB, validated in trials as a proxy for clinical outcomes includes tests of balance while standing, gait speed during a 4-minute walk, and strength. The latter is the test that measures time needed to rise from a chair five times.

They also showed consistent gains in other measures of physical functioning and quality of life by 12 weeks months.

The observed SPPB treatment effect is “impressive” and “compares very favorably with previously reported estimates,” observed an accompanying editorial from Stefan D. Anker, MD, PhD, of the German Center for Cardiovascular Research and Charité Universitätsmedizin, Berlin, and Andrew J.S. Coats, DM, of the University of Warwick, Coventry, England.

“Similarly, the between-group differences seen in 6-minute walk distance (34 m) and gait speed (0.12 m/s) are clinically meaningful and sizable.”

They propose that some of the substantial quality-of-life benefit in the intervention group “may be due to better physical performance, and that part may be due to improvements in psychosocial factors and mood. It appears that exercise also resulted in patients becoming happier, or at least less depressed, as evidenced by the positive results on the Geriatric Depression Scale.”
 

Similar results across most subgroups

In subgroup analyses, the intervention was successful against the standard-care approach in both men and women at all ages and regardless of ejection fraction; symptom status; and whether the patient had diabetes, ischemic heart disease, or atrial fibrillation, or was obese.

Clinical outcomes were not significantly different at 6 months. The rate of death from any cause was 13% for the intervention group and 10% for the control group. There were 194 and 213 hospitalizations from any cause, respectively.

Not included in the trial’s current publication but soon to be published, Dr. Kitzman said when interviewed, is a comparison of outcomes in patients with HFpEF and HFrEF. “We found at baseline that those with HFpEF had worse impairment in physical function, quality of life, and frailty. After the intervention, there appeared to be consistently larger improvements in all outcomes, including SPPB, 6-minute walk, qualify of life, and frailty, in HFpEF versus HFrEF.”

The signals of potential benefit in HFpEF extended to clinical endpoints, he said. In contrast to similar rates of all-cause rehospitalization in HFrEF, “in patients with HFpEF, rehospitalizations were 17% lower in the intervention group, compared to the control group.” Still, he noted, the interaction P value wasn’t significant.

However, Dr. Kitzman added, mortality in the intervention group, compared with the control group, was reduced by 35% among patients with HFpEF, “but was 250% higher in HFrEF,” with a significant interaction P value.

He was careful to note that, as a phase 2 trial, REHAB-HF was underpowered for clinical events, “and even the results in the HFpEF group should not be seen as adequate evidence to change clinical care.” They were from an exploratory analysis that included relatively few events.

“Because definitive demonstration of improvement in clinical events is critical for altering clinical care guidelines and for third-party payer reimbursement decisions, we believe that a subsequent phase 3 trial is needed and are currently planning toward that,” Dr. Kitzman said.

The study was supported by research grants from the National Institutes of Health, the Kermit Glenn Phillips II Chair in Cardiovascular Medicine, and the Oristano Family Fund at Wake Forest. Dr. Kitzman disclosed receiving consulting fees or honoraria from AbbVie, AstraZeneca, Bayer Healthcare, Boehringer Ingelheim, CinRx, Corviamedical, GlaxoSmithKline, and Merck; and having an unspecified relationship with Gilead. Dr. Handberg disclosed receiving grants from Aastom Biosciences, Abbott Laboratories, Amgen, Amorcyte, AstraZeneca, Biocardia, Boehringer Ingelheim, Capricor, Cytori Therapeutics, Department of Defense, Direct Flow Medical, Everyfit, Gilead, Ionis, Medtronic, Merck, Mesoblast, Relypsa, and Sanofi-Aventis. Dr. Bittner discloses receiving consulting fees or honoraria from Pfizer and Sanofi; receiving research grants from Amgen and The Medicines Company; and having unspecified relationships with AstraZeneca, DalCor, Esperion, and Sanofi-Aventis. Dr. Anker reported receiving grants and personal fees from Abbott Vascular and Vifor; personal fees from Bayer, Boehringer Ingelheim, Novartis, Servier, Cardiac Dimensions, Thermo Fisher Scientific, AstraZeneca, Occlutech, Actimed, and Respicardia. Dr. Coats disclosed receiving personal fees from AstraZeneca, Bayer, Boehringer Ingelheim, Menarini, Novartis, Nutricia, Servier, Vifor, Abbott, Actimed, Arena, Cardiac Dimensions, Corvia, CVRx, Enopace, ESN Cleer, Faraday, WL Gore, Impulse Dynamics, and Respicardia.

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

A new analysis of gene expression and protein content in lung and blood tissue suggests that certain variants of the ABO gene, which plays a central role in determining blood type, may also influence susceptibility to COVID-19. Researchers at the University of British Columbia, Vancouver, analyzed data from three studies to link gene and protein expression in lungs and blood with genetic regions associated with COVID-19 susceptibility.

“These genes may also prove to be good markers for disease as well as potential drug targets,” said lead author Ana Hernandez Cordero, PhD, postdoctoral fellow with the Center for Heart Lung Innovation, University of British Columbia, in a statement. Dr. Cordero presented the study at the American Thoracic Society’s virtual international conference.

Dr. Cordero noted that genomewide association studies have been used to identify genetic regions associated with COVID-19 susceptibility, but they cannot be used to identify specific genes. To pinpoint genes, the researchers employed integrated genomics, which combines Bayesian colocalization summary-based Mendelian randomization and Mendelian randomization.
 

Searching for candidate genes

The researchers combined genetic data and transcriptomics data, which are a measurement of the messenger RNA produced in a cell. Messenger RNA is used as a blueprint for protein production. The genetics data came from the COVID-19 Host Genetics Initiative genomewide association meta-analysis version 4 (patients with COVID-19 vs. patients without COVID-19). Blood transcriptomics data came from the INTERVAL study (n = 3301), and lung transcriptomics data came from the Lung eQTL study (n = 1038). “From the integration of these three datasets we identified the candidate genes that are most likely to influence COVID-19 through gene expression. We further investigated the most consistent candidate genes and tested the causal association between their plasma protein levels and COVID-19 susceptibility using Bayesian colocalization and Mendelian randomization,” said Dr. Cordero during her talk.

Susceptibility drivers

The researchers identified six genes expressed in the lung and five expressed in blood that colocalized with COVID-19 susceptibility loci. They found that an increase in plasma levels of ABO was associated with greater risk for COVID-19 (Mendelian randomization, P = .000025) and that expression of the SLC6A20 gene in the lung was also associated with higher COVID-19 risk. They also found novel associations at genes associated with respiratory diseases, such as asthma, as well as genes associated with the host immune responses, such as neutrophil and eosinophil counts.

Possibly protective?

Within the ABO gene, the research also turned up evidence that blood type O may be protective against COVID-19. “The most significant variant used for the Mendelian randomization test was in complete linkage disagreement with the variant responsible for the blood type O genotype, conferring reduced risk,” said Dr. Cordero.

The study’s method is a powerful technique, said Jeremy Alexander Hirota, PhD, who was asked to comment. “The present study uses integrative omics to determine COVID-19 susceptibility factors which would have been challenging to identify with a single technology,” said Dr. Hirota, who is an assistant professor of medicine at McMaster University, Hamilton, Ont.; an adjunct professor of biology at the University of Waterloo (Ont.); and an affiliate professor of medicine at the University of British Columbia. He trained with the senior author of the study but was not directly involved in the research.

The host response is widely believed to be most responsible for the symptoms of COVID-19, so it isn’t surprising that host genes can be identified, according to Dr. Hirota. The identification of variants in the ABO protein is interesting, though. It suggests ‘that systemic effects beyond respiratory mucosal immunity are a driver for susceptibility.’ To my understanding, ABO protein is not expressed in the respiratory mucosa, which is a common site of first contact for SARS-CoV-2. The links between blood ABO levels and initial infection of the respiratory mucosa by SARS-CoV-2 are unclear,” he said.
 

Severity link needed

Dr. Hirota also said that although the study points toward associations with susceptibility to COVID-19, it isn’t clear from the available data whether such associations are related to severity of disease. “If the [patients with gene variants] are more susceptible but [the disease is] less severe, then the results need to be interpreted accordingly. If the susceptibility is increased and the severity is also increased, maybe measured by increased risk for ICU admission, ventilator use, or mortality, then the work carries a much more important message. Future studies extending this work and integrating measures of severity are warranted to better understand the clinical utility of these findings for managing COVID-19 patients optimally,” said Dr. Hirota.

It’s also unclear whether the study populations are reflective of the populations that are currently at highest risk for COVID-19, such as residents of India, where the burden of disease is currently severe.

Dr. Cordero and Dr. Hirota disclosed no relevant financial relationships.

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

A new analysis of gene expression and protein content in lung and blood tissue suggests that certain variants of the ABO gene, which plays a central role in determining blood type, may also influence susceptibility to COVID-19. Researchers at the University of British Columbia, Vancouver, analyzed data from three studies to link gene and protein expression in lungs and blood with genetic regions associated with COVID-19 susceptibility.

“These genes may also prove to be good markers for disease as well as potential drug targets,” said lead author Ana Hernandez Cordero, PhD, postdoctoral fellow with the Center for Heart Lung Innovation, University of British Columbia, in a statement. Dr. Cordero presented the study at the American Thoracic Society’s virtual international conference.

Dr. Cordero noted that genomewide association studies have been used to identify genetic regions associated with COVID-19 susceptibility, but they cannot be used to identify specific genes. To pinpoint genes, the researchers employed integrated genomics, which combines Bayesian colocalization summary-based Mendelian randomization and Mendelian randomization.
 

Searching for candidate genes

The researchers combined genetic data and transcriptomics data, which are a measurement of the messenger RNA produced in a cell. Messenger RNA is used as a blueprint for protein production. The genetics data came from the COVID-19 Host Genetics Initiative genomewide association meta-analysis version 4 (patients with COVID-19 vs. patients without COVID-19). Blood transcriptomics data came from the INTERVAL study (n = 3301), and lung transcriptomics data came from the Lung eQTL study (n = 1038). “From the integration of these three datasets we identified the candidate genes that are most likely to influence COVID-19 through gene expression. We further investigated the most consistent candidate genes and tested the causal association between their plasma protein levels and COVID-19 susceptibility using Bayesian colocalization and Mendelian randomization,” said Dr. Cordero during her talk.

Susceptibility drivers

The researchers identified six genes expressed in the lung and five expressed in blood that colocalized with COVID-19 susceptibility loci. They found that an increase in plasma levels of ABO was associated with greater risk for COVID-19 (Mendelian randomization, P = .000025) and that expression of the SLC6A20 gene in the lung was also associated with higher COVID-19 risk. They also found novel associations at genes associated with respiratory diseases, such as asthma, as well as genes associated with the host immune responses, such as neutrophil and eosinophil counts.

Possibly protective?

Within the ABO gene, the research also turned up evidence that blood type O may be protective against COVID-19. “The most significant variant used for the Mendelian randomization test was in complete linkage disagreement with the variant responsible for the blood type O genotype, conferring reduced risk,” said Dr. Cordero.

The study’s method is a powerful technique, said Jeremy Alexander Hirota, PhD, who was asked to comment. “The present study uses integrative omics to determine COVID-19 susceptibility factors which would have been challenging to identify with a single technology,” said Dr. Hirota, who is an assistant professor of medicine at McMaster University, Hamilton, Ont.; an adjunct professor of biology at the University of Waterloo (Ont.); and an affiliate professor of medicine at the University of British Columbia. He trained with the senior author of the study but was not directly involved in the research.

The host response is widely believed to be most responsible for the symptoms of COVID-19, so it isn’t surprising that host genes can be identified, according to Dr. Hirota. The identification of variants in the ABO protein is interesting, though. It suggests ‘that systemic effects beyond respiratory mucosal immunity are a driver for susceptibility.’ To my understanding, ABO protein is not expressed in the respiratory mucosa, which is a common site of first contact for SARS-CoV-2. The links between blood ABO levels and initial infection of the respiratory mucosa by SARS-CoV-2 are unclear,” he said.
 

Severity link needed

Dr. Hirota also said that although the study points toward associations with susceptibility to COVID-19, it isn’t clear from the available data whether such associations are related to severity of disease. “If the [patients with gene variants] are more susceptible but [the disease is] less severe, then the results need to be interpreted accordingly. If the susceptibility is increased and the severity is also increased, maybe measured by increased risk for ICU admission, ventilator use, or mortality, then the work carries a much more important message. Future studies extending this work and integrating measures of severity are warranted to better understand the clinical utility of these findings for managing COVID-19 patients optimally,” said Dr. Hirota.

It’s also unclear whether the study populations are reflective of the populations that are currently at highest risk for COVID-19, such as residents of India, where the burden of disease is currently severe.

Dr. Cordero and Dr. Hirota disclosed no relevant financial relationships.

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

A new analysis of gene expression and protein content in lung and blood tissue suggests that certain variants of the ABO gene, which plays a central role in determining blood type, may also influence susceptibility to COVID-19. Researchers at the University of British Columbia, Vancouver, analyzed data from three studies to link gene and protein expression in lungs and blood with genetic regions associated with COVID-19 susceptibility.

“These genes may also prove to be good markers for disease as well as potential drug targets,” said lead author Ana Hernandez Cordero, PhD, postdoctoral fellow with the Center for Heart Lung Innovation, University of British Columbia, in a statement. Dr. Cordero presented the study at the American Thoracic Society’s virtual international conference.

Dr. Cordero noted that genomewide association studies have been used to identify genetic regions associated with COVID-19 susceptibility, but they cannot be used to identify specific genes. To pinpoint genes, the researchers employed integrated genomics, which combines Bayesian colocalization summary-based Mendelian randomization and Mendelian randomization.
 

Searching for candidate genes

The researchers combined genetic data and transcriptomics data, which are a measurement of the messenger RNA produced in a cell. Messenger RNA is used as a blueprint for protein production. The genetics data came from the COVID-19 Host Genetics Initiative genomewide association meta-analysis version 4 (patients with COVID-19 vs. patients without COVID-19). Blood transcriptomics data came from the INTERVAL study (n = 3301), and lung transcriptomics data came from the Lung eQTL study (n = 1038). “From the integration of these three datasets we identified the candidate genes that are most likely to influence COVID-19 through gene expression. We further investigated the most consistent candidate genes and tested the causal association between their plasma protein levels and COVID-19 susceptibility using Bayesian colocalization and Mendelian randomization,” said Dr. Cordero during her talk.

Susceptibility drivers

The researchers identified six genes expressed in the lung and five expressed in blood that colocalized with COVID-19 susceptibility loci. They found that an increase in plasma levels of ABO was associated with greater risk for COVID-19 (Mendelian randomization, P = .000025) and that expression of the SLC6A20 gene in the lung was also associated with higher COVID-19 risk. They also found novel associations at genes associated with respiratory diseases, such as asthma, as well as genes associated with the host immune responses, such as neutrophil and eosinophil counts.

Possibly protective?

Within the ABO gene, the research also turned up evidence that blood type O may be protective against COVID-19. “The most significant variant used for the Mendelian randomization test was in complete linkage disagreement with the variant responsible for the blood type O genotype, conferring reduced risk,” said Dr. Cordero.

The study’s method is a powerful technique, said Jeremy Alexander Hirota, PhD, who was asked to comment. “The present study uses integrative omics to determine COVID-19 susceptibility factors which would have been challenging to identify with a single technology,” said Dr. Hirota, who is an assistant professor of medicine at McMaster University, Hamilton, Ont.; an adjunct professor of biology at the University of Waterloo (Ont.); and an affiliate professor of medicine at the University of British Columbia. He trained with the senior author of the study but was not directly involved in the research.

The host response is widely believed to be most responsible for the symptoms of COVID-19, so it isn’t surprising that host genes can be identified, according to Dr. Hirota. The identification of variants in the ABO protein is interesting, though. It suggests ‘that systemic effects beyond respiratory mucosal immunity are a driver for susceptibility.’ To my understanding, ABO protein is not expressed in the respiratory mucosa, which is a common site of first contact for SARS-CoV-2. The links between blood ABO levels and initial infection of the respiratory mucosa by SARS-CoV-2 are unclear,” he said.
 

Severity link needed

Dr. Hirota also said that although the study points toward associations with susceptibility to COVID-19, it isn’t clear from the available data whether such associations are related to severity of disease. “If the [patients with gene variants] are more susceptible but [the disease is] less severe, then the results need to be interpreted accordingly. If the susceptibility is increased and the severity is also increased, maybe measured by increased risk for ICU admission, ventilator use, or mortality, then the work carries a much more important message. Future studies extending this work and integrating measures of severity are warranted to better understand the clinical utility of these findings for managing COVID-19 patients optimally,” said Dr. Hirota.

It’s also unclear whether the study populations are reflective of the populations that are currently at highest risk for COVID-19, such as residents of India, where the burden of disease is currently severe.

Dr. Cordero and Dr. Hirota disclosed no relevant financial relationships.

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

In new small cell lung cancer guidelines, the European Society of Medical Oncology calls for upfront atezolizumab or durvalumab in combination with four to six cycles of etoposide and a platinum for stage 4 disease.

The strong recommendation is based on two phase 3 trials that showed improved overall survival when the checkpoint inhibitors were added to standard chemotherapy. “With very similar results, and in the context of a severe unmet need, both trials justify the need for immunotherapy in the frontline setting” and established “new standards of care” for stage 4 disease, the group said. “Atezolizumab or durvalumab in combination with a platinum plus etoposide should be offered to all eligible chemotherapy-naive patients” with a performance status of 0-1, said the group led by Anne-Marie Dingemans, MD, PhD, a pulmonology professor at Maastricht (the Netherlands) University Medical Center.

Alessio Cortellini, MD, a consulting oncologist and visiting researcher at Imperial College London, said he strongly endorses the recommendation when asked for comment.

“The addition of a PD-L1 inhibitor to a platinum/etoposide backbone is the first strategy that has led to a significant benefit in terms of overall survival. After decades of disappointing results, the bar has” been raised, said Dr. Cortellini.
 

New inhibitor

EMSO also incorporated the new RNA polymerase II inhibitor lurbinectedin into their guidelines as an option for patients progressing on or after first-line platinum-based chemotherapy.

The agent was approved by the U.S. Food and Drug Administration in June 2020 for metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy.

The recommendations – more than 50 in all – are based on a literature review and expert opinion, and cover SCLC diagnosis, staging, treatment, and follow-up, with flowcharts outlining treatment pathways.

Atezolizumab earned the endorsement following the IMpower133 trial, which showed a median overall survival of 12.3 months for atezolizumab in combination with carboplatin and etoposide, versus 10.3 months on chemotherapy alone; 34% of the atezolizumab group was alive at 18 months versus 21% in the placebo arm.

The durvalumab recommendation is based on the CASPIAN trial, in which the addition of durvalumab to platinum plus etoposide improved median overall survival from 10.5 to 12.9 months; 32% of durvalumab patients were alive at 18 months versus 24.8% in the chemotherapy-alone arm.

ESMO said “it is important to stress that, in both trials,” patients were in good clinical condition with a median age in the early 60s, so relatively young for SCLC. Also, the modest benefits “clearly emphasize the need for” biomarkers that predict response in order to better select patients.

Immunotherapy has improved cancer treatment across many malignancies and continues to be actively investigated in SCLC, but so far only atezolizumab and durvalumab have phase 3 evidence of benefit.

Makers of the blockbuster checkpoint inhibitors nivolumab and pembrolizumab recently withdrew their FDA approval for stage 4 SCLC that’s progressed after platinum-based chemotherapy and at least one other line of therapy; phase 3 trials failed to confirm the modest survival benefit found in early studies.

Lurbinectedin earned its place in the guidelines based on a single-arm study with 105 relapsed patients that showed an overall response rate of 22.2% in platinum-resistant and 45% in platinum-sensitive patients, with a median overall survival of 9.3 months.

The jury is still out, however. A phase 3 trial of lurbinectedin plus doxorubicin versus topotecan or CAV [cyclophosphamide, adriamycin, and vincristine] for advanced recurrent disease failed to meet its endpoint of superior overall survival, according to a recent press release from the its maker.

“It might be a bit early to discuss” routine use of lurbinectedin, although having it available is good “since literally nothing works in the second line setting,” Dr. Cortellini said.

There was no external funding for the work. The authors had numerous ties to pharmaceutical companies, including Dr. Dingemans who reported adviser and speakers fees and/or research funding from Roche, Lilly, Bristol-Myers Squib, and others. Dr. Costellini reported speakers fees from Novartis, Astrazeneca, and Astellas and consultant payments from Bristol-Myers Squibb, Roche, MSD, and AstraZeneca.

aotto@mdedge.com

In new small cell lung cancer guidelines, the European Society of Medical Oncology calls for upfront atezolizumab or durvalumab in combination with four to six cycles of etoposide and a platinum for stage 4 disease.

The strong recommendation is based on two phase 3 trials that showed improved overall survival when the checkpoint inhibitors were added to standard chemotherapy. “With very similar results, and in the context of a severe unmet need, both trials justify the need for immunotherapy in the frontline setting” and established “new standards of care” for stage 4 disease, the group said. “Atezolizumab or durvalumab in combination with a platinum plus etoposide should be offered to all eligible chemotherapy-naive patients” with a performance status of 0-1, said the group led by Anne-Marie Dingemans, MD, PhD, a pulmonology professor at Maastricht (the Netherlands) University Medical Center.

Alessio Cortellini, MD, a consulting oncologist and visiting researcher at Imperial College London, said he strongly endorses the recommendation when asked for comment.

“The addition of a PD-L1 inhibitor to a platinum/etoposide backbone is the first strategy that has led to a significant benefit in terms of overall survival. After decades of disappointing results, the bar has” been raised, said Dr. Cortellini.
 

New inhibitor

EMSO also incorporated the new RNA polymerase II inhibitor lurbinectedin into their guidelines as an option for patients progressing on or after first-line platinum-based chemotherapy.

The agent was approved by the U.S. Food and Drug Administration in June 2020 for metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy.

The recommendations – more than 50 in all – are based on a literature review and expert opinion, and cover SCLC diagnosis, staging, treatment, and follow-up, with flowcharts outlining treatment pathways.

Atezolizumab earned the endorsement following the IMpower133 trial, which showed a median overall survival of 12.3 months for atezolizumab in combination with carboplatin and etoposide, versus 10.3 months on chemotherapy alone; 34% of the atezolizumab group was alive at 18 months versus 21% in the placebo arm.

The durvalumab recommendation is based on the CASPIAN trial, in which the addition of durvalumab to platinum plus etoposide improved median overall survival from 10.5 to 12.9 months; 32% of durvalumab patients were alive at 18 months versus 24.8% in the chemotherapy-alone arm.

ESMO said “it is important to stress that, in both trials,” patients were in good clinical condition with a median age in the early 60s, so relatively young for SCLC. Also, the modest benefits “clearly emphasize the need for” biomarkers that predict response in order to better select patients.

Immunotherapy has improved cancer treatment across many malignancies and continues to be actively investigated in SCLC, but so far only atezolizumab and durvalumab have phase 3 evidence of benefit.

Makers of the blockbuster checkpoint inhibitors nivolumab and pembrolizumab recently withdrew their FDA approval for stage 4 SCLC that’s progressed after platinum-based chemotherapy and at least one other line of therapy; phase 3 trials failed to confirm the modest survival benefit found in early studies.

Lurbinectedin earned its place in the guidelines based on a single-arm study with 105 relapsed patients that showed an overall response rate of 22.2% in platinum-resistant and 45% in platinum-sensitive patients, with a median overall survival of 9.3 months.

The jury is still out, however. A phase 3 trial of lurbinectedin plus doxorubicin versus topotecan or CAV [cyclophosphamide, adriamycin, and vincristine] for advanced recurrent disease failed to meet its endpoint of superior overall survival, according to a recent press release from the its maker.

“It might be a bit early to discuss” routine use of lurbinectedin, although having it available is good “since literally nothing works in the second line setting,” Dr. Cortellini said.

There was no external funding for the work. The authors had numerous ties to pharmaceutical companies, including Dr. Dingemans who reported adviser and speakers fees and/or research funding from Roche, Lilly, Bristol-Myers Squib, and others. Dr. Costellini reported speakers fees from Novartis, Astrazeneca, and Astellas and consultant payments from Bristol-Myers Squibb, Roche, MSD, and AstraZeneca.

aotto@mdedge.com

In new small cell lung cancer guidelines, the European Society of Medical Oncology calls for upfront atezolizumab or durvalumab in combination with four to six cycles of etoposide and a platinum for stage 4 disease.

The strong recommendation is based on two phase 3 trials that showed improved overall survival when the checkpoint inhibitors were added to standard chemotherapy. “With very similar results, and in the context of a severe unmet need, both trials justify the need for immunotherapy in the frontline setting” and established “new standards of care” for stage 4 disease, the group said. “Atezolizumab or durvalumab in combination with a platinum plus etoposide should be offered to all eligible chemotherapy-naive patients” with a performance status of 0-1, said the group led by Anne-Marie Dingemans, MD, PhD, a pulmonology professor at Maastricht (the Netherlands) University Medical Center.

Alessio Cortellini, MD, a consulting oncologist and visiting researcher at Imperial College London, said he strongly endorses the recommendation when asked for comment.

“The addition of a PD-L1 inhibitor to a platinum/etoposide backbone is the first strategy that has led to a significant benefit in terms of overall survival. After decades of disappointing results, the bar has” been raised, said Dr. Cortellini.
 

New inhibitor

EMSO also incorporated the new RNA polymerase II inhibitor lurbinectedin into their guidelines as an option for patients progressing on or after first-line platinum-based chemotherapy.

The agent was approved by the U.S. Food and Drug Administration in June 2020 for metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy.

The recommendations – more than 50 in all – are based on a literature review and expert opinion, and cover SCLC diagnosis, staging, treatment, and follow-up, with flowcharts outlining treatment pathways.

Atezolizumab earned the endorsement following the IMpower133 trial, which showed a median overall survival of 12.3 months for atezolizumab in combination with carboplatin and etoposide, versus 10.3 months on chemotherapy alone; 34% of the atezolizumab group was alive at 18 months versus 21% in the placebo arm.

The durvalumab recommendation is based on the CASPIAN trial, in which the addition of durvalumab to platinum plus etoposide improved median overall survival from 10.5 to 12.9 months; 32% of durvalumab patients were alive at 18 months versus 24.8% in the chemotherapy-alone arm.

ESMO said “it is important to stress that, in both trials,” patients were in good clinical condition with a median age in the early 60s, so relatively young for SCLC. Also, the modest benefits “clearly emphasize the need for” biomarkers that predict response in order to better select patients.

Immunotherapy has improved cancer treatment across many malignancies and continues to be actively investigated in SCLC, but so far only atezolizumab and durvalumab have phase 3 evidence of benefit.

Makers of the blockbuster checkpoint inhibitors nivolumab and pembrolizumab recently withdrew their FDA approval for stage 4 SCLC that’s progressed after platinum-based chemotherapy and at least one other line of therapy; phase 3 trials failed to confirm the modest survival benefit found in early studies.

Lurbinectedin earned its place in the guidelines based on a single-arm study with 105 relapsed patients that showed an overall response rate of 22.2% in platinum-resistant and 45% in platinum-sensitive patients, with a median overall survival of 9.3 months.

The jury is still out, however. A phase 3 trial of lurbinectedin plus doxorubicin versus topotecan or CAV [cyclophosphamide, adriamycin, and vincristine] for advanced recurrent disease failed to meet its endpoint of superior overall survival, according to a recent press release from the its maker.

“It might be a bit early to discuss” routine use of lurbinectedin, although having it available is good “since literally nothing works in the second line setting,” Dr. Cortellini said.

There was no external funding for the work. The authors had numerous ties to pharmaceutical companies, including Dr. Dingemans who reported adviser and speakers fees and/or research funding from Roche, Lilly, Bristol-Myers Squib, and others. Dr. Costellini reported speakers fees from Novartis, Astrazeneca, and Astellas and consultant payments from Bristol-Myers Squibb, Roche, MSD, and AstraZeneca.

aotto@mdedge.com

Medications typically used to treat opioid use disorder (OUD) may* also be effective for the growing public health problem of kratom addiction, new research shows.

Results of a comprehensive literature review and an expert survey suggest buprenorphine, naltrexone, and methadone may be effective for patients seeking help for kratom addiction, and if further research confirms these findings, the indication for OUD medications could potentially be expanded to include moderate-to-severe kratom addiction, study investigator Saeed Ahmed, MD, medical director of West Ridge Center at Rutland Regional Medical Center, Rutland, Vermont, said in an interview.

Dr. Ahmed, who practices general psychiatry and addiction psychiatry, presented the findings at the virtual American Psychiatric Association 2021 Annual Meeting.
 

Emerging public health problem

Kratom can be ingested in pill or capsule form or as an extract. Its leaves can be chewed or dried and powdered to make a tea. It can also be incorporated into topical creams, balms, or tinctures.

Products containing the substance are “readily available and legal for sale in many states and cities in the U.S.,” said Dr. Ahmed, adding that it can be purchased online or at local smoke shops and is increasingly used by individuals to self-treat a variety of conditions including pain, anxiety, and mood conditions and as an opioid substitute.

As reported by this news organization, a 2018 analysis conducted by the U.S. Food and Drug Administration showed kratom is, in fact, an opioid, a finding that garnered significant push-back from the American Kratom Association.

Kratom addiction is an “emerging public health problem,” said Dr. Ahmed, adding that in recent years the number of calls to poison control centers across the country has increased 52-fold – from one per month to two per day. He believes misinformation through social media has helped fuel its use.

Kratom use, the investigators note, can lead to muscle pain, weight loss, insomnia, hallucinations and, in some cases (particularly when combined with synthetic opioids or benzodiazepines), it can lead to respiratory depression, seizures, coma, and death.

In addition, the investigators note that to date, there are no guidelines on its management.

To investigate, the researchers conducted a systematic literature search for cases pertaining to maintenance treatment for kratom dependence. They also tapped into case reports and scientific posters from reliable online sources and conference proceedings. In addition, they conducted a survey of members from the American Society of Addiction Medicine (ASAM).

The researchers found 14 reports of long-term management of kratom addiction, half of which did not involve an OUD. It’s important to exclude OUDs to avoid possible confounding.

In most cases, buprenorphine was used, but in a few cases naltrexone or methadone were prescribed. All cases had a favorable outcome. Dr. Ahmed noted that buprenorphine maintenance doses appear to be lower than those required to effectively treat OUD.

With a response rate of 11.5% (82 respondents) the ASAM survey results showed 82.6% of respondents (n = 57) had experience managing KUD, including 27.5% (n = 19) who had kratom addiction only. Of these, 89.5% (n = 17-19), used buprenorphine to manage KUD and of these, 6 combined it with talk therapy.

Dr. Ahmed cautioned that the included cases varied significantly in terms of relevant data, including kratom dose and route of administration, toxicology screening used to monitor abstinence, and duration of maintenance follow-up.

Despite these limitations, the review and survey underscore the importance of including moderate to severe kratom dependence as an indication for current OUD medications, the researchers note.

Including kratom addiction as an indication for these medications is important, especially for patients who are heavily addicted, to meet DSM-5 diagnostic criteria for moderate or severe SUD, they add.

In addition, the researchers recommend that clinicians consider referring patients with moderate to severe kratom dependence for counseling or enrollment in 12-step addiction treatment programs.

A separate diagnosis?

Dr. Ahmed said he would like to see kratom dependence included in the DSM-5 as a separate entity because it is a botanical with properties similar to, but different from, traditional opioids.

“This will not only help to better inform clinicians about a diagnostic criteria encompassing problematic use and facilitate screening, but it will also pave the way for treatments to be explored for this diagnosable condition,” he said. Dr. Ahmed pointed to a review published in the Wisconsin Medical Journal earlier this year that explored potential treatments for kratom dependence.

Commenting on the study for an interview, Petros Levounis, MD, professor and chair, department of psychiatry, and associate dean for professional development, Rutgers New Jersey Medical School, Newark, said the authors “have done a great job reviewing the literature and asking experts” about kratom addiction treatment.

“The punchline of their study is that kratom behaves very much like an opioid and is treated like an opioid.”

Dr. Levounis noted that kratom dependence is so new that experts don’t know much about it. However, he added, emerging evidence suggests that kratom “should be considered an opioid more than anything else,” but specified that he does not believe it warrants its own diagnosis.

He noted that individual opioids don’t have their own diagnostic category and that opioid use disorder is an umbrella term that covers all of these drugs.

Dr. Ahmed and Dr. Levounis have disclosed no relevant financial relationships.

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

*Updated 5/18/2021

Medications typically used to treat opioid use disorder (OUD) may* also be effective for the growing public health problem of kratom addiction, new research shows.

Results of a comprehensive literature review and an expert survey suggest buprenorphine, naltrexone, and methadone may be effective for patients seeking help for kratom addiction, and if further research confirms these findings, the indication for OUD medications could potentially be expanded to include moderate-to-severe kratom addiction, study investigator Saeed Ahmed, MD, medical director of West Ridge Center at Rutland Regional Medical Center, Rutland, Vermont, said in an interview.

Dr. Ahmed, who practices general psychiatry and addiction psychiatry, presented the findings at the virtual American Psychiatric Association 2021 Annual Meeting.
 

Emerging public health problem

Kratom can be ingested in pill or capsule form or as an extract. Its leaves can be chewed or dried and powdered to make a tea. It can also be incorporated into topical creams, balms, or tinctures.

Products containing the substance are “readily available and legal for sale in many states and cities in the U.S.,” said Dr. Ahmed, adding that it can be purchased online or at local smoke shops and is increasingly used by individuals to self-treat a variety of conditions including pain, anxiety, and mood conditions and as an opioid substitute.

As reported by this news organization, a 2018 analysis conducted by the U.S. Food and Drug Administration showed kratom is, in fact, an opioid, a finding that garnered significant push-back from the American Kratom Association.

Kratom addiction is an “emerging public health problem,” said Dr. Ahmed, adding that in recent years the number of calls to poison control centers across the country has increased 52-fold – from one per month to two per day. He believes misinformation through social media has helped fuel its use.

Kratom use, the investigators note, can lead to muscle pain, weight loss, insomnia, hallucinations and, in some cases (particularly when combined with synthetic opioids or benzodiazepines), it can lead to respiratory depression, seizures, coma, and death.

In addition, the investigators note that to date, there are no guidelines on its management.

To investigate, the researchers conducted a systematic literature search for cases pertaining to maintenance treatment for kratom dependence. They also tapped into case reports and scientific posters from reliable online sources and conference proceedings. In addition, they conducted a survey of members from the American Society of Addiction Medicine (ASAM).

The researchers found 14 reports of long-term management of kratom addiction, half of which did not involve an OUD. It’s important to exclude OUDs to avoid possible confounding.

In most cases, buprenorphine was used, but in a few cases naltrexone or methadone were prescribed. All cases had a favorable outcome. Dr. Ahmed noted that buprenorphine maintenance doses appear to be lower than those required to effectively treat OUD.

With a response rate of 11.5% (82 respondents) the ASAM survey results showed 82.6% of respondents (n = 57) had experience managing KUD, including 27.5% (n = 19) who had kratom addiction only. Of these, 89.5% (n = 17-19), used buprenorphine to manage KUD and of these, 6 combined it with talk therapy.

Dr. Ahmed cautioned that the included cases varied significantly in terms of relevant data, including kratom dose and route of administration, toxicology screening used to monitor abstinence, and duration of maintenance follow-up.

Despite these limitations, the review and survey underscore the importance of including moderate to severe kratom dependence as an indication for current OUD medications, the researchers note.

Including kratom addiction as an indication for these medications is important, especially for patients who are heavily addicted, to meet DSM-5 diagnostic criteria for moderate or severe SUD, they add.

In addition, the researchers recommend that clinicians consider referring patients with moderate to severe kratom dependence for counseling or enrollment in 12-step addiction treatment programs.

A separate diagnosis?

Dr. Ahmed said he would like to see kratom dependence included in the DSM-5 as a separate entity because it is a botanical with properties similar to, but different from, traditional opioids.

“This will not only help to better inform clinicians about a diagnostic criteria encompassing problematic use and facilitate screening, but it will also pave the way for treatments to be explored for this diagnosable condition,” he said. Dr. Ahmed pointed to a review published in the Wisconsin Medical Journal earlier this year that explored potential treatments for kratom dependence.

Commenting on the study for an interview, Petros Levounis, MD, professor and chair, department of psychiatry, and associate dean for professional development, Rutgers New Jersey Medical School, Newark, said the authors “have done a great job reviewing the literature and asking experts” about kratom addiction treatment.

“The punchline of their study is that kratom behaves very much like an opioid and is treated like an opioid.”

Dr. Levounis noted that kratom dependence is so new that experts don’t know much about it. However, he added, emerging evidence suggests that kratom “should be considered an opioid more than anything else,” but specified that he does not believe it warrants its own diagnosis.

He noted that individual opioids don’t have their own diagnostic category and that opioid use disorder is an umbrella term that covers all of these drugs.

Dr. Ahmed and Dr. Levounis have disclosed no relevant financial relationships.

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

*Updated 5/18/2021

Medications typically used to treat opioid use disorder (OUD) may* also be effective for the growing public health problem of kratom addiction, new research shows.

Results of a comprehensive literature review and an expert survey suggest buprenorphine, naltrexone, and methadone may be effective for patients seeking help for kratom addiction, and if further research confirms these findings, the indication for OUD medications could potentially be expanded to include moderate-to-severe kratom addiction, study investigator Saeed Ahmed, MD, medical director of West Ridge Center at Rutland Regional Medical Center, Rutland, Vermont, said in an interview.

Dr. Ahmed, who practices general psychiatry and addiction psychiatry, presented the findings at the virtual American Psychiatric Association 2021 Annual Meeting.
 

Emerging public health problem

Kratom can be ingested in pill or capsule form or as an extract. Its leaves can be chewed or dried and powdered to make a tea. It can also be incorporated into topical creams, balms, or tinctures.

Products containing the substance are “readily available and legal for sale in many states and cities in the U.S.,” said Dr. Ahmed, adding that it can be purchased online or at local smoke shops and is increasingly used by individuals to self-treat a variety of conditions including pain, anxiety, and mood conditions and as an opioid substitute.

As reported by this news organization, a 2018 analysis conducted by the U.S. Food and Drug Administration showed kratom is, in fact, an opioid, a finding that garnered significant push-back from the American Kratom Association.

Kratom addiction is an “emerging public health problem,” said Dr. Ahmed, adding that in recent years the number of calls to poison control centers across the country has increased 52-fold – from one per month to two per day. He believes misinformation through social media has helped fuel its use.

Kratom use, the investigators note, can lead to muscle pain, weight loss, insomnia, hallucinations and, in some cases (particularly when combined with synthetic opioids or benzodiazepines), it can lead to respiratory depression, seizures, coma, and death.

In addition, the investigators note that to date, there are no guidelines on its management.

To investigate, the researchers conducted a systematic literature search for cases pertaining to maintenance treatment for kratom dependence. They also tapped into case reports and scientific posters from reliable online sources and conference proceedings. In addition, they conducted a survey of members from the American Society of Addiction Medicine (ASAM).

The researchers found 14 reports of long-term management of kratom addiction, half of which did not involve an OUD. It’s important to exclude OUDs to avoid possible confounding.

In most cases, buprenorphine was used, but in a few cases naltrexone or methadone were prescribed. All cases had a favorable outcome. Dr. Ahmed noted that buprenorphine maintenance doses appear to be lower than those required to effectively treat OUD.

With a response rate of 11.5% (82 respondents) the ASAM survey results showed 82.6% of respondents (n = 57) had experience managing KUD, including 27.5% (n = 19) who had kratom addiction only. Of these, 89.5% (n = 17-19), used buprenorphine to manage KUD and of these, 6 combined it with talk therapy.

Dr. Ahmed cautioned that the included cases varied significantly in terms of relevant data, including kratom dose and route of administration, toxicology screening used to monitor abstinence, and duration of maintenance follow-up.

Despite these limitations, the review and survey underscore the importance of including moderate to severe kratom dependence as an indication for current OUD medications, the researchers note.

Including kratom addiction as an indication for these medications is important, especially for patients who are heavily addicted, to meet DSM-5 diagnostic criteria for moderate or severe SUD, they add.

In addition, the researchers recommend that clinicians consider referring patients with moderate to severe kratom dependence for counseling or enrollment in 12-step addiction treatment programs.

A separate diagnosis?

Dr. Ahmed said he would like to see kratom dependence included in the DSM-5 as a separate entity because it is a botanical with properties similar to, but different from, traditional opioids.

“This will not only help to better inform clinicians about a diagnostic criteria encompassing problematic use and facilitate screening, but it will also pave the way for treatments to be explored for this diagnosable condition,” he said. Dr. Ahmed pointed to a review published in the Wisconsin Medical Journal earlier this year that explored potential treatments for kratom dependence.

Commenting on the study for an interview, Petros Levounis, MD, professor and chair, department of psychiatry, and associate dean for professional development, Rutgers New Jersey Medical School, Newark, said the authors “have done a great job reviewing the literature and asking experts” about kratom addiction treatment.

“The punchline of their study is that kratom behaves very much like an opioid and is treated like an opioid.”

Dr. Levounis noted that kratom dependence is so new that experts don’t know much about it. However, he added, emerging evidence suggests that kratom “should be considered an opioid more than anything else,” but specified that he does not believe it warrants its own diagnosis.

He noted that individual opioids don’t have their own diagnostic category and that opioid use disorder is an umbrella term that covers all of these drugs.

Dr. Ahmed and Dr. Levounis have disclosed no relevant financial relationships.

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

*Updated 5/18/2021

A majority of Mohs surgeons have adopted telemedicine during the COVID-19 pandemic, a new survey finds, but only half expressed interest in making it a permanent part of their practices.

A variety of factors combine to make it “very difficult for surgeons to make long-term plans for implementing telemedicine in their practices,” said Mario Maruthur, MD, who presented the findings at the annual meeting of the American College of Mohs Surgery. “Telemedicine likely has a role in Mohs practices, particularly with postop follow-up visits. However, postpandemic reimbursement and regulatory issues need to be formally laid out before Mohs surgeons are able to incorporate it into their permanent work flow.”

Dr. Maruthur, a Mohs surgery and dermatologic oncology fellow at Memorial Sloan Kettering Cancer Center, New York, and colleagues sent a survey to ACMS members in September and October 2020. “We saw first-hand in our surgical practice that telemedicine quickly became an important tool when the pandemic surged in the spring of 2020,” he said. Considering that surgical practices are highly dependent on in-person visits, the impetus for this study was to assess to what degree Mohs practices from across the spectrum, including academic and private practices, embraced telemedicine during the pandemic, and “what these surgical practices used telemedicine for, how it was received by their patients, which telemedicine platforms were most often utilized, and lastly, what are their plans if any for incorporating telemedicine into their surgical practices after the pandemic subsides.”

The researchers received responses from 115 surgeons representing all regions of the country (40% Northeast, 21% South, 21% Midwest, and 18% West). Half practiced in urban areas (37%) and large cities (13%), and 40% were in an academic setting versus 36% in a single-specialty private practice.

More than 70% of the respondents said their case load fell by at least 75% during the initial surge of the pandemic; 80% turned to telemedicine, compared with just 23% who relied on the technology prior to the pandemic. The most commonly used telemedicine technologies were FaceTime, Zoom, Doximity, and Epic.

Mohs surgeons reported most commonly using telemedicine for postsurgery management (77% of the total 115 responses). “Telemedicine is a great fit for this category of visits as they allow the surgeon to view the surgical site and answer any questions they patient may have,” Dr. Maruthur said. “If the surgeon does suspect a postop infection or other concern based on a patient’s signs or symptoms, they can easily schedule the patient for an in-person assessment. We suspect that postop follow-up visits may be the best candidate for long-term use of telemedicine in Mohs surgery practices.”

Surgeons also reported using telemedicine for “spot checks” (61%) and surgical consultations (59%).

However, Dr. Maruther noted that preoperative assessments and spot checks can be difficult to perform using telemedicine. “The quality of the video image is not always great, patients can have a difficult time pointing the camera at the right spot and at the right distance. Even appreciating the actual size of the lesion are all difficult over a video encounter. And there is a lot of information gleaned from in-person physical examination, such as whether the lesion is fixed to a deeper structure and whether there are any nearby scars or other suspicious lesions.”

Nearly three-quarters of the surgeons using the technology said most or all patients were receptive to telemedicine.

However, the surgeons reported multiple barriers to the use of telemedicine: Limitations when compared with physical exams (88%), fitting it into the work flow (58%), patient response and training (57%), reimbursement concerns (50%), implementation of the technology (37%), regulations such as HIPAA (24%), training of staff (17%), and licensing (8%).

In an interview, Sumaira Z. Aasi, MD, director of Mohs and dermatologic surgery, Stanford University, agreed that there are many obstacles to routine use of telemedicine by Mohs surgeons. “As surgeons, we rely on the physical and tactile exam to get a sense of the size and extent of the cancer and characteristics such as the laxity of the surrounding tissue whether the tumor is fixed,” she said. “It is very difficult to access this on a telemedicine visit.”

In addition, she said, “many of our patients are in the elderly population, and some may not be comfortable using this technology. Also, it’s not a work flow that we are comfortable or familiar with. And I think that the technology has to improve to allow for better resolution of images as we ‘examine’ patients through a telemedicine visit.”

She added that “another con is there is a reliance on having the patient point out lesions of concern. Many cancers are picked by a careful in-person examination by a qualified physician/dermatologist/Mohs surgeon when the lesion is quite small or subtle and not even noticed by the patient themselves. This approach invariably leads to earlier biopsies and earlier treatments that can prevent morbidity and save health care money.”

On the other hand, she said, telemedicine “may save patients some time and money in terms of the effort and cost of transportation to come in for simpler postoperative medical visits that are often short in their very nature, such as postop check-ups.”

Most of the surgeons surveyed (69%) said telemedicine probably or definitely deserves a place in the practice Mohs surgery, but only 50% said they’d like to or would definitely pursue giving telemedicine a role in their practices once the pandemic is over.

“At the start of the pandemic, many regulations in areas such as HIPAA were eased, and reimbursements were increased, which allowed telemedicine to be quickly adopted,” Dr. Maruther said. “The government and payers have yet to decide which regulations and reimbursements will be in place after the pandemic. That makes it very difficult for surgeons to make long-term plans for implementing telemedicine in their practices.”

Dr. Aasi predicted that telemedicine will become more appealing to patients and physicians as it its technology and usability improves. More familiarity with its use will also be helpful, she said, and surgeons will be more receptive as it’s incorporated into efficient daily work flow.

The study was funded in part by the National Institutes of Health.

A majority of Mohs surgeons have adopted telemedicine during the COVID-19 pandemic, a new survey finds, but only half expressed interest in making it a permanent part of their practices.

A variety of factors combine to make it “very difficult for surgeons to make long-term plans for implementing telemedicine in their practices,” said Mario Maruthur, MD, who presented the findings at the annual meeting of the American College of Mohs Surgery. “Telemedicine likely has a role in Mohs practices, particularly with postop follow-up visits. However, postpandemic reimbursement and regulatory issues need to be formally laid out before Mohs surgeons are able to incorporate it into their permanent work flow.”

Dr. Maruthur, a Mohs surgery and dermatologic oncology fellow at Memorial Sloan Kettering Cancer Center, New York, and colleagues sent a survey to ACMS members in September and October 2020. “We saw first-hand in our surgical practice that telemedicine quickly became an important tool when the pandemic surged in the spring of 2020,” he said. Considering that surgical practices are highly dependent on in-person visits, the impetus for this study was to assess to what degree Mohs practices from across the spectrum, including academic and private practices, embraced telemedicine during the pandemic, and “what these surgical practices used telemedicine for, how it was received by their patients, which telemedicine platforms were most often utilized, and lastly, what are their plans if any for incorporating telemedicine into their surgical practices after the pandemic subsides.”

The researchers received responses from 115 surgeons representing all regions of the country (40% Northeast, 21% South, 21% Midwest, and 18% West). Half practiced in urban areas (37%) and large cities (13%), and 40% were in an academic setting versus 36% in a single-specialty private practice.

More than 70% of the respondents said their case load fell by at least 75% during the initial surge of the pandemic; 80% turned to telemedicine, compared with just 23% who relied on the technology prior to the pandemic. The most commonly used telemedicine technologies were FaceTime, Zoom, Doximity, and Epic.

Mohs surgeons reported most commonly using telemedicine for postsurgery management (77% of the total 115 responses). “Telemedicine is a great fit for this category of visits as they allow the surgeon to view the surgical site and answer any questions they patient may have,” Dr. Maruthur said. “If the surgeon does suspect a postop infection or other concern based on a patient’s signs or symptoms, they can easily schedule the patient for an in-person assessment. We suspect that postop follow-up visits may be the best candidate for long-term use of telemedicine in Mohs surgery practices.”

Surgeons also reported using telemedicine for “spot checks” (61%) and surgical consultations (59%).

However, Dr. Maruther noted that preoperative assessments and spot checks can be difficult to perform using telemedicine. “The quality of the video image is not always great, patients can have a difficult time pointing the camera at the right spot and at the right distance. Even appreciating the actual size of the lesion are all difficult over a video encounter. And there is a lot of information gleaned from in-person physical examination, such as whether the lesion is fixed to a deeper structure and whether there are any nearby scars or other suspicious lesions.”

Nearly three-quarters of the surgeons using the technology said most or all patients were receptive to telemedicine.

However, the surgeons reported multiple barriers to the use of telemedicine: Limitations when compared with physical exams (88%), fitting it into the work flow (58%), patient response and training (57%), reimbursement concerns (50%), implementation of the technology (37%), regulations such as HIPAA (24%), training of staff (17%), and licensing (8%).

In an interview, Sumaira Z. Aasi, MD, director of Mohs and dermatologic surgery, Stanford University, agreed that there are many obstacles to routine use of telemedicine by Mohs surgeons. “As surgeons, we rely on the physical and tactile exam to get a sense of the size and extent of the cancer and characteristics such as the laxity of the surrounding tissue whether the tumor is fixed,” she said. “It is very difficult to access this on a telemedicine visit.”

In addition, she said, “many of our patients are in the elderly population, and some may not be comfortable using this technology. Also, it’s not a work flow that we are comfortable or familiar with. And I think that the technology has to improve to allow for better resolution of images as we ‘examine’ patients through a telemedicine visit.”

She added that “another con is there is a reliance on having the patient point out lesions of concern. Many cancers are picked by a careful in-person examination by a qualified physician/dermatologist/Mohs surgeon when the lesion is quite small or subtle and not even noticed by the patient themselves. This approach invariably leads to earlier biopsies and earlier treatments that can prevent morbidity and save health care money.”

On the other hand, she said, telemedicine “may save patients some time and money in terms of the effort and cost of transportation to come in for simpler postoperative medical visits that are often short in their very nature, such as postop check-ups.”

Most of the surgeons surveyed (69%) said telemedicine probably or definitely deserves a place in the practice Mohs surgery, but only 50% said they’d like to or would definitely pursue giving telemedicine a role in their practices once the pandemic is over.

“At the start of the pandemic, many regulations in areas such as HIPAA were eased, and reimbursements were increased, which allowed telemedicine to be quickly adopted,” Dr. Maruther said. “The government and payers have yet to decide which regulations and reimbursements will be in place after the pandemic. That makes it very difficult for surgeons to make long-term plans for implementing telemedicine in their practices.”

Dr. Aasi predicted that telemedicine will become more appealing to patients and physicians as it its technology and usability improves. More familiarity with its use will also be helpful, she said, and surgeons will be more receptive as it’s incorporated into efficient daily work flow.

The study was funded in part by the National Institutes of Health.

A majority of Mohs surgeons have adopted telemedicine during the COVID-19 pandemic, a new survey finds, but only half expressed interest in making it a permanent part of their practices.

A variety of factors combine to make it “very difficult for surgeons to make long-term plans for implementing telemedicine in their practices,” said Mario Maruthur, MD, who presented the findings at the annual meeting of the American College of Mohs Surgery. “Telemedicine likely has a role in Mohs practices, particularly with postop follow-up visits. However, postpandemic reimbursement and regulatory issues need to be formally laid out before Mohs surgeons are able to incorporate it into their permanent work flow.”

Dr. Maruthur, a Mohs surgery and dermatologic oncology fellow at Memorial Sloan Kettering Cancer Center, New York, and colleagues sent a survey to ACMS members in September and October 2020. “We saw first-hand in our surgical practice that telemedicine quickly became an important tool when the pandemic surged in the spring of 2020,” he said. Considering that surgical practices are highly dependent on in-person visits, the impetus for this study was to assess to what degree Mohs practices from across the spectrum, including academic and private practices, embraced telemedicine during the pandemic, and “what these surgical practices used telemedicine for, how it was received by their patients, which telemedicine platforms were most often utilized, and lastly, what are their plans if any for incorporating telemedicine into their surgical practices after the pandemic subsides.”

The researchers received responses from 115 surgeons representing all regions of the country (40% Northeast, 21% South, 21% Midwest, and 18% West). Half practiced in urban areas (37%) and large cities (13%), and 40% were in an academic setting versus 36% in a single-specialty private practice.

More than 70% of the respondents said their case load fell by at least 75% during the initial surge of the pandemic; 80% turned to telemedicine, compared with just 23% who relied on the technology prior to the pandemic. The most commonly used telemedicine technologies were FaceTime, Zoom, Doximity, and Epic.

Mohs surgeons reported most commonly using telemedicine for postsurgery management (77% of the total 115 responses). “Telemedicine is a great fit for this category of visits as they allow the surgeon to view the surgical site and answer any questions they patient may have,” Dr. Maruthur said. “If the surgeon does suspect a postop infection or other concern based on a patient’s signs or symptoms, they can easily schedule the patient for an in-person assessment. We suspect that postop follow-up visits may be the best candidate for long-term use of telemedicine in Mohs surgery practices.”

Surgeons also reported using telemedicine for “spot checks” (61%) and surgical consultations (59%).

However, Dr. Maruther noted that preoperative assessments and spot checks can be difficult to perform using telemedicine. “The quality of the video image is not always great, patients can have a difficult time pointing the camera at the right spot and at the right distance. Even appreciating the actual size of the lesion are all difficult over a video encounter. And there is a lot of information gleaned from in-person physical examination, such as whether the lesion is fixed to a deeper structure and whether there are any nearby scars or other suspicious lesions.”

Nearly three-quarters of the surgeons using the technology said most or all patients were receptive to telemedicine.

However, the surgeons reported multiple barriers to the use of telemedicine: Limitations when compared with physical exams (88%), fitting it into the work flow (58%), patient response and training (57%), reimbursement concerns (50%), implementation of the technology (37%), regulations such as HIPAA (24%), training of staff (17%), and licensing (8%).

In an interview, Sumaira Z. Aasi, MD, director of Mohs and dermatologic surgery, Stanford University, agreed that there are many obstacles to routine use of telemedicine by Mohs surgeons. “As surgeons, we rely on the physical and tactile exam to get a sense of the size and extent of the cancer and characteristics such as the laxity of the surrounding tissue whether the tumor is fixed,” she said. “It is very difficult to access this on a telemedicine visit.”

In addition, she said, “many of our patients are in the elderly population, and some may not be comfortable using this technology. Also, it’s not a work flow that we are comfortable or familiar with. And I think that the technology has to improve to allow for better resolution of images as we ‘examine’ patients through a telemedicine visit.”

She added that “another con is there is a reliance on having the patient point out lesions of concern. Many cancers are picked by a careful in-person examination by a qualified physician/dermatologist/Mohs surgeon when the lesion is quite small or subtle and not even noticed by the patient themselves. This approach invariably leads to earlier biopsies and earlier treatments that can prevent morbidity and save health care money.”

On the other hand, she said, telemedicine “may save patients some time and money in terms of the effort and cost of transportation to come in for simpler postoperative medical visits that are often short in their very nature, such as postop check-ups.”

Most of the surgeons surveyed (69%) said telemedicine probably or definitely deserves a place in the practice Mohs surgery, but only 50% said they’d like to or would definitely pursue giving telemedicine a role in their practices once the pandemic is over.

“At the start of the pandemic, many regulations in areas such as HIPAA were eased, and reimbursements were increased, which allowed telemedicine to be quickly adopted,” Dr. Maruther said. “The government and payers have yet to decide which regulations and reimbursements will be in place after the pandemic. That makes it very difficult for surgeons to make long-term plans for implementing telemedicine in their practices.”

Dr. Aasi predicted that telemedicine will become more appealing to patients and physicians as it its technology and usability improves. More familiarity with its use will also be helpful, she said, and surgeons will be more receptive as it’s incorporated into efficient daily work flow.

The study was funded in part by the National Institutes of Health.

Questions over the cardiovascular benefits shown in the REDUCE-IT trial with icosapent ethyl, a high-dose eicosapentaenoic acid (EPA) product, have been reignited with a new analysis from the STRENGTH trial showing no benefit of a high-dose combined omega-3 fatty acid product in patients who achieved the highest EPA levels and no harm in those with the highest levels of docosahexaenoic acid (DHA).

STRENGTH investigator Steven Nissen, MD, said these new results add to concerns about the positive result in the previously reported REDUCE-IT trial and suggest that “there is no strong evidence of a benefit of fish oil in preventing major cardiovascular events.”

But Dr. Nissen, who is chair of the department of cardiovascular medicine at the Cleveland Clinic in Ohio, pointed out evidence of harm, with both REDUCE-IT and STRENGTH showing an increase in atrial fibrillation with the high-dose omega-3 fatty acid products.

“Fish oils increase the risk of atrial fibrillation substantially, and there is no solid evidence that they help the heart in any way,” he stated.

The new STRENGTH analysis was presented at the annual scientific sessions of the American College of Cardiology. and was simultaneously published in JAMA Cardiology.

The REDUCE-IT trial showed a large 25% relative-risk reduction in cardiovascular events in patients taking icosapent ethyl (Vascepa, Amarin), a high-dose purified formulation of EPA, compared with patients taking a mineral oil placebo. But a similar trial, STRENGTH, showed no effect of a similar high dose of the mixed EPA/DHA product (Epanova, AstraZeneca), compared with a corn oil placebo.

The different results from these two studies have led to many questions about how the benefits seen in REDUCE-IT were brought about, and why they weren’t replicated in the STRENGTH study.

Dr. Nissen noted that several hypotheses have been proposed. These include a potential adverse effect of the mineral oil placebo in the REDUCE-IT trial, which may have elevated risk in the placebo treatment group and led to a false-positive result for icosapent ethyl. Another possibility is that the moderately higher plasma levels of EPA achieved in REDUCE-IT were responsible for the observed benefits or that the coadministration of DHA in STRENGTH may have counteracted the potential beneficial effects of EPA.

The current post hoc analysis of STRENGTH was conducted to address these latter two possibilities. It aimed to assess the association between cardiovascular outcomes and achieved levels of EPA, DHA, or changes in levels of these fatty acids.

“In our new analysis, among patients treated with fish oil, we found no evidence that EPA is beneficial or that DHA is harmful,” Dr. Nissen said.

Results of the new analysis showed an absence of a benefit from achieving high levels of EPA or harm from achieving high levels of DHA which, the authors say, “strengthens the concerns that the choice of comparator may have influenced the divergent results observed in the two trials.”

“Unlike corn oil, which is inert, mineral oil has major adverse effects, increasing LDL by 10.9% and CRP [C-reactive protein] by 32% in the REDUCE-IT trial,” Dr. Nissen said. “If you give a toxic placebo, then the active drug may falsely look really good.”  

The STRENGTH trial randomly assigned 13,078 individuals at high risk for major cardiovascular events to receive 4 g daily of the EPA/DHA combined product (omega-3 carboxylic acid) or corn oil as the placebo. Main results, reported previously, showed no difference between the two groups in terms of the primary outcome – a composite of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or unstable angina requiring hospitalization.

The current analysis, in 10,382 patients with available omega-3 fatty acid levels, looked at event rates according to tertiles of achieved EPA and DHA levels. The median plasma EPA level for patients taking the omega-3 product was 89 mcg/mL, with the top tertile achieving levels of 151 mcg/mL (a 443% increase). Dr. Nissen pointed out that this was higher than the median level of EPA reported in the REDUCE-IT trial (144 mcg/mL).

The median level of DHA was 91 mcg/mL, rising to 118 mcg/mL (a 68% increase) in the top tertile in the STRENGTH analysis.

Results showed no difference in the occurrence of the prespecified primary outcome among patients treated with omega-3 carboxylic acid who were in the top tertile of achieved EPA levels at 1 year (event rate, 11.3%), compared with patients treated with corn oil (11.0%), a nonsignificant difference (hazard ratio, 0.98; P = .81).

For DHA, patients in the top tertile of achieved DHA levels had an event rate of 11.4% vs. 11.0% in the corn oil group, also a nonsignificant difference (HR, 1.02; P = .85)    

Sensitivity analyses based on the highest tertile of change in EPA or DHA levels showed similarly neutral results.

Because plasma levels may not reflect tissue levels of EPA or DHA, additional analyses assessed red blood cell EPA and DHA levels, neither of which showed any evidence of benefit or harm.

“These findings suggest that supplementation of omega-3 fatty acids in high-risk cardiovascular patients is neutral even at the highest achieved levels,” Dr. Nissen said. “And, in the context of increased risk of atrial fibrillation in omega-3 trials, they cast uncertainty over whether there is net benefit or harm with any omega-3 preparation,” he concluded.

He suggested that the choice of placebo comparator may play an important role in determining outcome for trials of omega-3 products, adding that further research is needed with trials specifically designed to compare corn oil with mineral oil and compare purified EPA with other formulations of omega-3 fatty acids.

At an press conference, Dr. Nissen said he could not recommend use of omega-3 fatty acid products for cardiovascular risk reduction given the uncertainty over the benefit in REDUCE-IT.

“We need replication, and the problem is STRENGTH did not replicate REDUCE-IT,” he stated.

 REDUCE-IT investigator responds

The discussant of the STRENGTH analysis at the ACC presentation, Deepak L. Bhatt, MD, who was lead investigator of the REDUCE-IT trial, suggested that one conclusion could be that “an absence of a relationship in a negative trial doesn’t tell us that much other than that specific drug doesn’t work.”

Dr. Bhatt, who is executive director of interventional cardiovascular programs at Brigham and Women’s Hospital Heart & Vascular Center, Boston, said in an interview that comparisons should not be made between different trials using different products.  

“I commend the STRENGTH investigators on a well-conducted trial that provided a definitive answer about the specific drug they studied, finding no benefit. But in a completely negative trial, I wouldn’t necessarily expect to see a relationship between any biomarker and outcome,” he said.

“With respect to icosapent ethyl (pure EPA), every cardiovascular trial to date has been positive: REDUCE-IT (randomized, placebo-controlled), JELIS (randomized, no placebo), EVAPORATE (randomized, placebo-controlled), CHERRY (randomized, no placebo), and some smaller ones,” Dr. Bhatt added. “Both REDUCE-IT and JELIS found associations between higher levels of EPA and lower rates of cardiovascular events, suggesting that higher EPA levels attained specifically with icosapent ethyl are beneficial.”

Pointing out that all the glucagonlike peptide–1 agonists lower glucose, for example, but not all reduce cardiovascular events, Dr. Bhatt said it was best to focus on clinical trial results and not overly focus on biomarker changes.

“Yes, the drug in STRENGTH raised EPA (and raised DHA, as well as lowering triglycerides), but the drug in REDUCE-IT and JELIS raised EPA much more, without raising DHA – and more importantly, the increase in EPA was via a totally different drug, with many different properties,” he added.

In his discussion of the study at the ACC presentation, Dr. Bhatt pointed out that in the STRENGTH trial overall there was no reduction in major adverse cardiovascular events despite a 19% reduction in triglycerides, which he said was a “very interesting disconnect.” He asked Dr. Nissen what he thought the reason was for the observation in this analysis of no relationship between EPA or DHA level and triglyceride reduction. 

Dr. Nissen said that was an interesting point. “When we look at the two trials, they both reduced triglyceride levels by an almost identical amount, 19%, but we don’t see a relationship with that and EPA levels achieved.” He suggested this may be because of different threshold levels.

Dr. Bhatt also noted that high-intensity statin use was lower in the patients with higher EPA levels in the STRENGTH analysis, but Dr. Nissen countered: “I don’t think that was enough of a difference to explain the lack of an effect.”

Invited commentator on the new analysis at an ACC press conference, Eileen Handberg, PhD, said it was important to try to understand the reasons behind the different results of the STRENGTH and REDUCE-IT trials. “These new findings are important because they explain potentially why these outcomes are different,” she stated.

Dr. Handberg, who is professor of medicine at the University of Florida, Gainesville, said she hoped the additional research called for by Dr. Nissen would go ahead as a head-to-head study of the two omega-3 products or of the two different placebo oils.

The STRENGTH trial was sponsored by Astra Zeneca. Dr. Nissen reports research grants from AbbVie, Amgen, Astra Zeneca, Eli Lilly, Esperion Therapeutics, MEDTRONIC, MyoKardia, Novartis, Novo Nordisk, Pfizer, and Silence Therapeutics. Dr. Bhatt reports constant fees/honoraria from CellProthera, Elsevier Practice Update Cardiology, K2P, Level Ex, Medtelligence, MJH Life Sciences, and WebMD; data safety monitoring board activities with Contego; other roles with TobeSoft, Belvoir Publications, Cardax, Cereno Scientific, Clinical Cardiology, Elsevier, HMP Global, Janssen Pharmaceuticals, Journal of Invasive Cardiology, Medscape Cardiology, Merck, MyoKardia, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Slack Publications/Cardiology Research Foundation; and research grants from Abbott, Afimmune, Amarin, Amgen, Astra Zeneca, Bayer Healthcare Pharmaceuticals, Boehringer Ingelheim Pharmaceuticals,  Bristol-Myers Squibb, Cardax, Chiesi, Eisai, Eli Lilly, Ethicon, FlowCo, Forest Laboratories, Fractyl, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Lexicon, MEDTRONIC, MyoKardia, Owkin, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi Aventis, Synaptic, Takeda, and The Medicines Company.  

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

Questions over the cardiovascular benefits shown in the REDUCE-IT trial with icosapent ethyl, a high-dose eicosapentaenoic acid (EPA) product, have been reignited with a new analysis from the STRENGTH trial showing no benefit of a high-dose combined omega-3 fatty acid product in patients who achieved the highest EPA levels and no harm in those with the highest levels of docosahexaenoic acid (DHA).

STRENGTH investigator Steven Nissen, MD, said these new results add to concerns about the positive result in the previously reported REDUCE-IT trial and suggest that “there is no strong evidence of a benefit of fish oil in preventing major cardiovascular events.”

But Dr. Nissen, who is chair of the department of cardiovascular medicine at the Cleveland Clinic in Ohio, pointed out evidence of harm, with both REDUCE-IT and STRENGTH showing an increase in atrial fibrillation with the high-dose omega-3 fatty acid products.

“Fish oils increase the risk of atrial fibrillation substantially, and there is no solid evidence that they help the heart in any way,” he stated.

The new STRENGTH analysis was presented at the annual scientific sessions of the American College of Cardiology. and was simultaneously published in JAMA Cardiology.

The REDUCE-IT trial showed a large 25% relative-risk reduction in cardiovascular events in patients taking icosapent ethyl (Vascepa, Amarin), a high-dose purified formulation of EPA, compared with patients taking a mineral oil placebo. But a similar trial, STRENGTH, showed no effect of a similar high dose of the mixed EPA/DHA product (Epanova, AstraZeneca), compared with a corn oil placebo.

The different results from these two studies have led to many questions about how the benefits seen in REDUCE-IT were brought about, and why they weren’t replicated in the STRENGTH study.

Dr. Nissen noted that several hypotheses have been proposed. These include a potential adverse effect of the mineral oil placebo in the REDUCE-IT trial, which may have elevated risk in the placebo treatment group and led to a false-positive result for icosapent ethyl. Another possibility is that the moderately higher plasma levels of EPA achieved in REDUCE-IT were responsible for the observed benefits or that the coadministration of DHA in STRENGTH may have counteracted the potential beneficial effects of EPA.

The current post hoc analysis of STRENGTH was conducted to address these latter two possibilities. It aimed to assess the association between cardiovascular outcomes and achieved levels of EPA, DHA, or changes in levels of these fatty acids.

“In our new analysis, among patients treated with fish oil, we found no evidence that EPA is beneficial or that DHA is harmful,” Dr. Nissen said.

Results of the new analysis showed an absence of a benefit from achieving high levels of EPA or harm from achieving high levels of DHA which, the authors say, “strengthens the concerns that the choice of comparator may have influenced the divergent results observed in the two trials.”

“Unlike corn oil, which is inert, mineral oil has major adverse effects, increasing LDL by 10.9% and CRP [C-reactive protein] by 32% in the REDUCE-IT trial,” Dr. Nissen said. “If you give a toxic placebo, then the active drug may falsely look really good.”  

The STRENGTH trial randomly assigned 13,078 individuals at high risk for major cardiovascular events to receive 4 g daily of the EPA/DHA combined product (omega-3 carboxylic acid) or corn oil as the placebo. Main results, reported previously, showed no difference between the two groups in terms of the primary outcome – a composite of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or unstable angina requiring hospitalization.

The current analysis, in 10,382 patients with available omega-3 fatty acid levels, looked at event rates according to tertiles of achieved EPA and DHA levels. The median plasma EPA level for patients taking the omega-3 product was 89 mcg/mL, with the top tertile achieving levels of 151 mcg/mL (a 443% increase). Dr. Nissen pointed out that this was higher than the median level of EPA reported in the REDUCE-IT trial (144 mcg/mL).

The median level of DHA was 91 mcg/mL, rising to 118 mcg/mL (a 68% increase) in the top tertile in the STRENGTH analysis.

Results showed no difference in the occurrence of the prespecified primary outcome among patients treated with omega-3 carboxylic acid who were in the top tertile of achieved EPA levels at 1 year (event rate, 11.3%), compared with patients treated with corn oil (11.0%), a nonsignificant difference (hazard ratio, 0.98; P = .81).

For DHA, patients in the top tertile of achieved DHA levels had an event rate of 11.4% vs. 11.0% in the corn oil group, also a nonsignificant difference (HR, 1.02; P = .85)    

Sensitivity analyses based on the highest tertile of change in EPA or DHA levels showed similarly neutral results.

Because plasma levels may not reflect tissue levels of EPA or DHA, additional analyses assessed red blood cell EPA and DHA levels, neither of which showed any evidence of benefit or harm.

“These findings suggest that supplementation of omega-3 fatty acids in high-risk cardiovascular patients is neutral even at the highest achieved levels,” Dr. Nissen said. “And, in the context of increased risk of atrial fibrillation in omega-3 trials, they cast uncertainty over whether there is net benefit or harm with any omega-3 preparation,” he concluded.

He suggested that the choice of placebo comparator may play an important role in determining outcome for trials of omega-3 products, adding that further research is needed with trials specifically designed to compare corn oil with mineral oil and compare purified EPA with other formulations of omega-3 fatty acids.

At an press conference, Dr. Nissen said he could not recommend use of omega-3 fatty acid products for cardiovascular risk reduction given the uncertainty over the benefit in REDUCE-IT.

“We need replication, and the problem is STRENGTH did not replicate REDUCE-IT,” he stated.

 REDUCE-IT investigator responds

The discussant of the STRENGTH analysis at the ACC presentation, Deepak L. Bhatt, MD, who was lead investigator of the REDUCE-IT trial, suggested that one conclusion could be that “an absence of a relationship in a negative trial doesn’t tell us that much other than that specific drug doesn’t work.”

Dr. Bhatt, who is executive director of interventional cardiovascular programs at Brigham and Women’s Hospital Heart & Vascular Center, Boston, said in an interview that comparisons should not be made between different trials using different products.  

“I commend the STRENGTH investigators on a well-conducted trial that provided a definitive answer about the specific drug they studied, finding no benefit. But in a completely negative trial, I wouldn’t necessarily expect to see a relationship between any biomarker and outcome,” he said.

“With respect to icosapent ethyl (pure EPA), every cardiovascular trial to date has been positive: REDUCE-IT (randomized, placebo-controlled), JELIS (randomized, no placebo), EVAPORATE (randomized, placebo-controlled), CHERRY (randomized, no placebo), and some smaller ones,” Dr. Bhatt added. “Both REDUCE-IT and JELIS found associations between higher levels of EPA and lower rates of cardiovascular events, suggesting that higher EPA levels attained specifically with icosapent ethyl are beneficial.”

Pointing out that all the glucagonlike peptide–1 agonists lower glucose, for example, but not all reduce cardiovascular events, Dr. Bhatt said it was best to focus on clinical trial results and not overly focus on biomarker changes.

“Yes, the drug in STRENGTH raised EPA (and raised DHA, as well as lowering triglycerides), but the drug in REDUCE-IT and JELIS raised EPA much more, without raising DHA – and more importantly, the increase in EPA was via a totally different drug, with many different properties,” he added.

In his discussion of the study at the ACC presentation, Dr. Bhatt pointed out that in the STRENGTH trial overall there was no reduction in major adverse cardiovascular events despite a 19% reduction in triglycerides, which he said was a “very interesting disconnect.” He asked Dr. Nissen what he thought the reason was for the observation in this analysis of no relationship between EPA or DHA level and triglyceride reduction. 

Dr. Nissen said that was an interesting point. “When we look at the two trials, they both reduced triglyceride levels by an almost identical amount, 19%, but we don’t see a relationship with that and EPA levels achieved.” He suggested this may be because of different threshold levels.

Dr. Bhatt also noted that high-intensity statin use was lower in the patients with higher EPA levels in the STRENGTH analysis, but Dr. Nissen countered: “I don’t think that was enough of a difference to explain the lack of an effect.”

Invited commentator on the new analysis at an ACC press conference, Eileen Handberg, PhD, said it was important to try to understand the reasons behind the different results of the STRENGTH and REDUCE-IT trials. “These new findings are important because they explain potentially why these outcomes are different,” she stated.

Dr. Handberg, who is professor of medicine at the University of Florida, Gainesville, said she hoped the additional research called for by Dr. Nissen would go ahead as a head-to-head study of the two omega-3 products or of the two different placebo oils.

The STRENGTH trial was sponsored by Astra Zeneca. Dr. Nissen reports research grants from AbbVie, Amgen, Astra Zeneca, Eli Lilly, Esperion Therapeutics, MEDTRONIC, MyoKardia, Novartis, Novo Nordisk, Pfizer, and Silence Therapeutics. Dr. Bhatt reports constant fees/honoraria from CellProthera, Elsevier Practice Update Cardiology, K2P, Level Ex, Medtelligence, MJH Life Sciences, and WebMD; data safety monitoring board activities with Contego; other roles with TobeSoft, Belvoir Publications, Cardax, Cereno Scientific, Clinical Cardiology, Elsevier, HMP Global, Janssen Pharmaceuticals, Journal of Invasive Cardiology, Medscape Cardiology, Merck, MyoKardia, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Slack Publications/Cardiology Research Foundation; and research grants from Abbott, Afimmune, Amarin, Amgen, Astra Zeneca, Bayer Healthcare Pharmaceuticals, Boehringer Ingelheim Pharmaceuticals,  Bristol-Myers Squibb, Cardax, Chiesi, Eisai, Eli Lilly, Ethicon, FlowCo, Forest Laboratories, Fractyl, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Lexicon, MEDTRONIC, MyoKardia, Owkin, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi Aventis, Synaptic, Takeda, and The Medicines Company.  

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

Questions over the cardiovascular benefits shown in the REDUCE-IT trial with icosapent ethyl, a high-dose eicosapentaenoic acid (EPA) product, have been reignited with a new analysis from the STRENGTH trial showing no benefit of a high-dose combined omega-3 fatty acid product in patients who achieved the highest EPA levels and no harm in those with the highest levels of docosahexaenoic acid (DHA).

STRENGTH investigator Steven Nissen, MD, said these new results add to concerns about the positive result in the previously reported REDUCE-IT trial and suggest that “there is no strong evidence of a benefit of fish oil in preventing major cardiovascular events.”

But Dr. Nissen, who is chair of the department of cardiovascular medicine at the Cleveland Clinic in Ohio, pointed out evidence of harm, with both REDUCE-IT and STRENGTH showing an increase in atrial fibrillation with the high-dose omega-3 fatty acid products.

“Fish oils increase the risk of atrial fibrillation substantially, and there is no solid evidence that they help the heart in any way,” he stated.

The new STRENGTH analysis was presented at the annual scientific sessions of the American College of Cardiology. and was simultaneously published in JAMA Cardiology.

The REDUCE-IT trial showed a large 25% relative-risk reduction in cardiovascular events in patients taking icosapent ethyl (Vascepa, Amarin), a high-dose purified formulation of EPA, compared with patients taking a mineral oil placebo. But a similar trial, STRENGTH, showed no effect of a similar high dose of the mixed EPA/DHA product (Epanova, AstraZeneca), compared with a corn oil placebo.

The different results from these two studies have led to many questions about how the benefits seen in REDUCE-IT were brought about, and why they weren’t replicated in the STRENGTH study.

Dr. Nissen noted that several hypotheses have been proposed. These include a potential adverse effect of the mineral oil placebo in the REDUCE-IT trial, which may have elevated risk in the placebo treatment group and led to a false-positive result for icosapent ethyl. Another possibility is that the moderately higher plasma levels of EPA achieved in REDUCE-IT were responsible for the observed benefits or that the coadministration of DHA in STRENGTH may have counteracted the potential beneficial effects of EPA.

The current post hoc analysis of STRENGTH was conducted to address these latter two possibilities. It aimed to assess the association between cardiovascular outcomes and achieved levels of EPA, DHA, or changes in levels of these fatty acids.

“In our new analysis, among patients treated with fish oil, we found no evidence that EPA is beneficial or that DHA is harmful,” Dr. Nissen said.

Results of the new analysis showed an absence of a benefit from achieving high levels of EPA or harm from achieving high levels of DHA which, the authors say, “strengthens the concerns that the choice of comparator may have influenced the divergent results observed in the two trials.”

“Unlike corn oil, which is inert, mineral oil has major adverse effects, increasing LDL by 10.9% and CRP [C-reactive protein] by 32% in the REDUCE-IT trial,” Dr. Nissen said. “If you give a toxic placebo, then the active drug may falsely look really good.”  

The STRENGTH trial randomly assigned 13,078 individuals at high risk for major cardiovascular events to receive 4 g daily of the EPA/DHA combined product (omega-3 carboxylic acid) or corn oil as the placebo. Main results, reported previously, showed no difference between the two groups in terms of the primary outcome – a composite of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or unstable angina requiring hospitalization.

The current analysis, in 10,382 patients with available omega-3 fatty acid levels, looked at event rates according to tertiles of achieved EPA and DHA levels. The median plasma EPA level for patients taking the omega-3 product was 89 mcg/mL, with the top tertile achieving levels of 151 mcg/mL (a 443% increase). Dr. Nissen pointed out that this was higher than the median level of EPA reported in the REDUCE-IT trial (144 mcg/mL).

The median level of DHA was 91 mcg/mL, rising to 118 mcg/mL (a 68% increase) in the top tertile in the STRENGTH analysis.

Results showed no difference in the occurrence of the prespecified primary outcome among patients treated with omega-3 carboxylic acid who were in the top tertile of achieved EPA levels at 1 year (event rate, 11.3%), compared with patients treated with corn oil (11.0%), a nonsignificant difference (hazard ratio, 0.98; P = .81).

For DHA, patients in the top tertile of achieved DHA levels had an event rate of 11.4% vs. 11.0% in the corn oil group, also a nonsignificant difference (HR, 1.02; P = .85)    

Sensitivity analyses based on the highest tertile of change in EPA or DHA levels showed similarly neutral results.

Because plasma levels may not reflect tissue levels of EPA or DHA, additional analyses assessed red blood cell EPA and DHA levels, neither of which showed any evidence of benefit or harm.

“These findings suggest that supplementation of omega-3 fatty acids in high-risk cardiovascular patients is neutral even at the highest achieved levels,” Dr. Nissen said. “And, in the context of increased risk of atrial fibrillation in omega-3 trials, they cast uncertainty over whether there is net benefit or harm with any omega-3 preparation,” he concluded.

He suggested that the choice of placebo comparator may play an important role in determining outcome for trials of omega-3 products, adding that further research is needed with trials specifically designed to compare corn oil with mineral oil and compare purified EPA with other formulations of omega-3 fatty acids.

At an press conference, Dr. Nissen said he could not recommend use of omega-3 fatty acid products for cardiovascular risk reduction given the uncertainty over the benefit in REDUCE-IT.

“We need replication, and the problem is STRENGTH did not replicate REDUCE-IT,” he stated.

 REDUCE-IT investigator responds

The discussant of the STRENGTH analysis at the ACC presentation, Deepak L. Bhatt, MD, who was lead investigator of the REDUCE-IT trial, suggested that one conclusion could be that “an absence of a relationship in a negative trial doesn’t tell us that much other than that specific drug doesn’t work.”

Dr. Bhatt, who is executive director of interventional cardiovascular programs at Brigham and Women’s Hospital Heart & Vascular Center, Boston, said in an interview that comparisons should not be made between different trials using different products.  

“I commend the STRENGTH investigators on a well-conducted trial that provided a definitive answer about the specific drug they studied, finding no benefit. But in a completely negative trial, I wouldn’t necessarily expect to see a relationship between any biomarker and outcome,” he said.

“With respect to icosapent ethyl (pure EPA), every cardiovascular trial to date has been positive: REDUCE-IT (randomized, placebo-controlled), JELIS (randomized, no placebo), EVAPORATE (randomized, placebo-controlled), CHERRY (randomized, no placebo), and some smaller ones,” Dr. Bhatt added. “Both REDUCE-IT and JELIS found associations between higher levels of EPA and lower rates of cardiovascular events, suggesting that higher EPA levels attained specifically with icosapent ethyl are beneficial.”

Pointing out that all the glucagonlike peptide–1 agonists lower glucose, for example, but not all reduce cardiovascular events, Dr. Bhatt said it was best to focus on clinical trial results and not overly focus on biomarker changes.

“Yes, the drug in STRENGTH raised EPA (and raised DHA, as well as lowering triglycerides), but the drug in REDUCE-IT and JELIS raised EPA much more, without raising DHA – and more importantly, the increase in EPA was via a totally different drug, with many different properties,” he added.

In his discussion of the study at the ACC presentation, Dr. Bhatt pointed out that in the STRENGTH trial overall there was no reduction in major adverse cardiovascular events despite a 19% reduction in triglycerides, which he said was a “very interesting disconnect.” He asked Dr. Nissen what he thought the reason was for the observation in this analysis of no relationship between EPA or DHA level and triglyceride reduction. 

Dr. Nissen said that was an interesting point. “When we look at the two trials, they both reduced triglyceride levels by an almost identical amount, 19%, but we don’t see a relationship with that and EPA levels achieved.” He suggested this may be because of different threshold levels.

Dr. Bhatt also noted that high-intensity statin use was lower in the patients with higher EPA levels in the STRENGTH analysis, but Dr. Nissen countered: “I don’t think that was enough of a difference to explain the lack of an effect.”

Invited commentator on the new analysis at an ACC press conference, Eileen Handberg, PhD, said it was important to try to understand the reasons behind the different results of the STRENGTH and REDUCE-IT trials. “These new findings are important because they explain potentially why these outcomes are different,” she stated.

Dr. Handberg, who is professor of medicine at the University of Florida, Gainesville, said she hoped the additional research called for by Dr. Nissen would go ahead as a head-to-head study of the two omega-3 products or of the two different placebo oils.

The STRENGTH trial was sponsored by Astra Zeneca. Dr. Nissen reports research grants from AbbVie, Amgen, Astra Zeneca, Eli Lilly, Esperion Therapeutics, MEDTRONIC, MyoKardia, Novartis, Novo Nordisk, Pfizer, and Silence Therapeutics. Dr. Bhatt reports constant fees/honoraria from CellProthera, Elsevier Practice Update Cardiology, K2P, Level Ex, Medtelligence, MJH Life Sciences, and WebMD; data safety monitoring board activities with Contego; other roles with TobeSoft, Belvoir Publications, Cardax, Cereno Scientific, Clinical Cardiology, Elsevier, HMP Global, Janssen Pharmaceuticals, Journal of Invasive Cardiology, Medscape Cardiology, Merck, MyoKardia, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Slack Publications/Cardiology Research Foundation; and research grants from Abbott, Afimmune, Amarin, Amgen, Astra Zeneca, Bayer Healthcare Pharmaceuticals, Boehringer Ingelheim Pharmaceuticals,  Bristol-Myers Squibb, Cardax, Chiesi, Eisai, Eli Lilly, Ethicon, FlowCo, Forest Laboratories, Fractyl, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Lexicon, MEDTRONIC, MyoKardia, Owkin, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi Aventis, Synaptic, Takeda, and The Medicines Company.  

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

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

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

Courtesy American College of Cardiology

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

A former ‘hot concept’

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

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

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

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

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

Denervation coupled with a single, daily three-drug pill

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

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

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

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

But each method has its advantages, he added.

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

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

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

mzoler@mdedge.com

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

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

Courtesy American College of Cardiology

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

A former ‘hot concept’

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

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

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

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

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

Denervation coupled with a single, daily three-drug pill

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

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

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

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

But each method has its advantages, he added.

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

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

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

mzoler@mdedge.com

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

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

Courtesy American College of Cardiology

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

A former ‘hot concept’

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

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

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

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

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

Denervation coupled with a single, daily three-drug pill

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

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

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

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

But each method has its advantages, he added.

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

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

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

mzoler@mdedge.com