Ted Bosworth

In an early phase multicenter clinical study, large reductions in lipoprotein(a), or Lp(a), were achieved with a well-tolerated small interfering RNA (siRNA) therapeutic, lepodisiran.

The reductions in serum Lp(a) in patients receiving lepodisiran were dose dependent but adverse events were not, said Steven E. Nissen, MD, professor of medicine at the Cleveland Clinic Lerner College of Medicine.

Rather, drug-related adverse events “were uncommon and generally similar across all lepodisiran doses and the placebo group,” reported Dr. Nissen, who pointed out that safety and tolerability were the primary endpoints and purpose of this phase 1 study.
 

Lp(a) strongly associated with CV risk

Similar to LDL cholesterol (LDL-C), elevated levels of serum Lp(a) have been associated with major adverse cardiac events (MACE). In a 2022 review article that summarized pathophysiological, observational, and genetic studies, Lp(a) was found to be implicated in vascular inflammation, atherogenesis, calcification, and thrombosis.

Furthermore, Lp(a) has been associated with residual risk of cardiovascular (CV) events even after tight control of other risk factors, including elevated LDL-C, Dr. Nissen said.

So far, no well-tolerated therapy has been found to be effective for reducing Lp(a), but siRNA is a novel and attractive approach, according to Dr. Nissen, who presented these results at the annual scientific sessions of the American Heart Association. They were also published online in JAMA.

By silencing target genes, siRNA therapies can inhibit a basic step in a given pathological process. In this case, lepodisiran silences the LPA gene to halt encoding of apolipoprotein(a), which plays a key role in Lp(a) production.

Lepodisiran is not the only treatment in development for Lp(a), noted the AHA-invited discussant Michelle L. O’Donoghue, MD, chair in cardiology, Brigham and Women’s Hospital, Boston. She mentioned several other siRNA therapies, including olpasiran that was effective in a phase 2 trial she led and published in the New England Journal of Medicine.

Drugs with different mechanisms, such as the antisense oligonucleotide pelacarsen, showed activity when tested earlier this year in a phase 1 study. No study has yet been conducted to link reductions in Lp(a) with CV event risk reduction.

The current study with lepodisiran was conducted with the participation of five clinical research sites in the United States and Singapore. Participants between the ages of 18 and 65 years were enrolled if they had a serum Lp(a) of at least 75 nmol/L (30 mg/dL), which is considered moderately elevated.

They were excluded if they had CV disease or significant risk factors, including a blood pressure greater than 160/40 mm Hg, impaired renal function (eGFR < 60 mL/min per 1.73 m²), or tobacco use (> 10 cigarettes/day).

Of 340 candidates screened, 48 were randomly assigned to one placebo or six lepodisiran groups. There were 12 participants in the placebo group and 6 in each of the lepodisiran dosing groups (4 mg, 12 mg, 32 mg, 96 mg, 304 mg, and 608 mg). All doses and placebo were administered subcutaneously one time with a planned follow-up of up to 48 weeks.
 

Safety profile is placebo-like

The single most common adverse event, shared by those randomly assigned to placebo, was injection-site reaction. There were no adverse events, including laboratory abnormalities, that were persistent and clearly different for those assigned to any dose of lepodisiran relative to placebo.

The maximum median percentage change in serum Lp(a) out to day 337 of follow-up was 5% reduction in the placebo group. In the active treatment groups, the reductions were 41% on 4 mg, 59% on 12 mg, 76% on 32 mg, 96% on 304 mg, and 97% on 608 mg.

These reductions were generally sustained for as long as therapy was maintained. Maximal reductions were reached at day 85 in the 4-mg group but were achieved by day 29 in the 605-mg group, Dr. Nissen reported. In fact, serum Lp(a) was undetectable in the 605-mg group at day 29 and remained so until day 281.

Currently, there is no practical treatment for Lp(a). The only potential exception, apheresis, is “cumbersome” to perform and must be repeated for sustained reductions. Niacin and PCSK9 inhibitors are known to provide modest reductions in Lp(a), but Dr. Nissen said they are too modest to expect a meaningful clinical benefit.
 

Lp(a) not responsive to lifestyle changes

Statins as well as all lifestyle modifications, including diet, have been shown to have “little or no effect,” Dr. Nissen said.

The safety and the evidence so far of sustained Lp(a) lowering has already led to a phase 2 trial, according to Dr. Nissen, but the more important test for the future of lepodisiran will be studies powered to confirm reductions in MACE. Lepodisiran may finally allow that hypothesis to be tested.

“I think a lot of us have been waiting a long time for evidence that we can reliably reduce Lp(a),” said Karol Watson, MD, PhD, who has a research interest in lipids and is a professor of medicine at the University of California, Los Angeles.

Although she conceded that the overwhelming evidence that Lp(a) is a risk factor does not ensure that any specific Lp(a)-lowering therapy will be clinically viable, she suggested this drug is a promising candidate to move this field forward.

“At the highest doses, lepodisiran is not just lowering Lp(a), it appears to be getting rid of it,” she said.

Dr. O’Donoghue said that the phase 1 results suggest lepodisiran might have a somewhat longer duration of action than other siRNA therapies studied for Lp(a) so far, but said larger trials are needed to determine whether the growing number of drugs in this class differ in ways that are clinically meaningful.

Overall, the excitement in this field is probably mostly driven by the fact that there are so many promising therapies for Lp(a) that address the target in so many unique ways. Dr. O’Donoghue cited, as an example, a gene-editing therapy called CTX320 that showed impressive effects in an animal study presented at the AHA meeting as a poster. She called the pipeline for treating Lp(a) “rich.”

Elevated Lp(a) is genetically determined, so levels do not generally change over time, said Donald Lloyd-Jones, MD, chair of the department of preventive medicine, Northwestern Medicine, Chicago.

“It is not affected by your diet. It is not affected by your exercise. What your level is will be the level you will have for the rest of your life,” he said. Generally, it is recommended to have Lp(a) measured just once to more accurately calculate cardiovascular risk, but Dr. Lloyd-Jones predicted that this lipid subfraction might be measured more frequently to verify control if a therapeutic becomes available.

Dr. Nissen agreed. Estimating that 64 million people in the United States have significantly elevated Lp(a), he expects this risk to be addressed as a specific and independent target in CV risk management when and if it becomes treatable.

Dr. Nissen reported financial relationships with Novartis, Silence Therapeutics, and Eli Lilly, which provided funding for this trial. Dr. Watson reported financial relationships with Amgen, Boehringer Ingelheim, Lilly, and Novartis. Dr. Lloyd-Jones disclosed no relevant financial relationships.

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

In an early phase multicenter clinical study, large reductions in lipoprotein(a), or Lp(a), were achieved with a well-tolerated small interfering RNA (siRNA) therapeutic, lepodisiran.

The reductions in serum Lp(a) in patients receiving lepodisiran were dose dependent but adverse events were not, said Steven E. Nissen, MD, professor of medicine at the Cleveland Clinic Lerner College of Medicine.

Rather, drug-related adverse events “were uncommon and generally similar across all lepodisiran doses and the placebo group,” reported Dr. Nissen, who pointed out that safety and tolerability were the primary endpoints and purpose of this phase 1 study.
 

Lp(a) strongly associated with CV risk

Similar to LDL cholesterol (LDL-C), elevated levels of serum Lp(a) have been associated with major adverse cardiac events (MACE). In a 2022 review article that summarized pathophysiological, observational, and genetic studies, Lp(a) was found to be implicated in vascular inflammation, atherogenesis, calcification, and thrombosis.

Furthermore, Lp(a) has been associated with residual risk of cardiovascular (CV) events even after tight control of other risk factors, including elevated LDL-C, Dr. Nissen said.

So far, no well-tolerated therapy has been found to be effective for reducing Lp(a), but siRNA is a novel and attractive approach, according to Dr. Nissen, who presented these results at the annual scientific sessions of the American Heart Association. They were also published online in JAMA.

By silencing target genes, siRNA therapies can inhibit a basic step in a given pathological process. In this case, lepodisiran silences the LPA gene to halt encoding of apolipoprotein(a), which plays a key role in Lp(a) production.

Lepodisiran is not the only treatment in development for Lp(a), noted the AHA-invited discussant Michelle L. O’Donoghue, MD, chair in cardiology, Brigham and Women’s Hospital, Boston. She mentioned several other siRNA therapies, including olpasiran that was effective in a phase 2 trial she led and published in the New England Journal of Medicine.

Drugs with different mechanisms, such as the antisense oligonucleotide pelacarsen, showed activity when tested earlier this year in a phase 1 study. No study has yet been conducted to link reductions in Lp(a) with CV event risk reduction.

The current study with lepodisiran was conducted with the participation of five clinical research sites in the United States and Singapore. Participants between the ages of 18 and 65 years were enrolled if they had a serum Lp(a) of at least 75 nmol/L (30 mg/dL), which is considered moderately elevated.

They were excluded if they had CV disease or significant risk factors, including a blood pressure greater than 160/40 mm Hg, impaired renal function (eGFR < 60 mL/min per 1.73 m²), or tobacco use (> 10 cigarettes/day).

Of 340 candidates screened, 48 were randomly assigned to one placebo or six lepodisiran groups. There were 12 participants in the placebo group and 6 in each of the lepodisiran dosing groups (4 mg, 12 mg, 32 mg, 96 mg, 304 mg, and 608 mg). All doses and placebo were administered subcutaneously one time with a planned follow-up of up to 48 weeks.
 

Safety profile is placebo-like

The single most common adverse event, shared by those randomly assigned to placebo, was injection-site reaction. There were no adverse events, including laboratory abnormalities, that were persistent and clearly different for those assigned to any dose of lepodisiran relative to placebo.

The maximum median percentage change in serum Lp(a) out to day 337 of follow-up was 5% reduction in the placebo group. In the active treatment groups, the reductions were 41% on 4 mg, 59% on 12 mg, 76% on 32 mg, 96% on 304 mg, and 97% on 608 mg.

These reductions were generally sustained for as long as therapy was maintained. Maximal reductions were reached at day 85 in the 4-mg group but were achieved by day 29 in the 605-mg group, Dr. Nissen reported. In fact, serum Lp(a) was undetectable in the 605-mg group at day 29 and remained so until day 281.

Currently, there is no practical treatment for Lp(a). The only potential exception, apheresis, is “cumbersome” to perform and must be repeated for sustained reductions. Niacin and PCSK9 inhibitors are known to provide modest reductions in Lp(a), but Dr. Nissen said they are too modest to expect a meaningful clinical benefit.
 

Lp(a) not responsive to lifestyle changes

Statins as well as all lifestyle modifications, including diet, have been shown to have “little or no effect,” Dr. Nissen said.

The safety and the evidence so far of sustained Lp(a) lowering has already led to a phase 2 trial, according to Dr. Nissen, but the more important test for the future of lepodisiran will be studies powered to confirm reductions in MACE. Lepodisiran may finally allow that hypothesis to be tested.

“I think a lot of us have been waiting a long time for evidence that we can reliably reduce Lp(a),” said Karol Watson, MD, PhD, who has a research interest in lipids and is a professor of medicine at the University of California, Los Angeles.

Although she conceded that the overwhelming evidence that Lp(a) is a risk factor does not ensure that any specific Lp(a)-lowering therapy will be clinically viable, she suggested this drug is a promising candidate to move this field forward.

“At the highest doses, lepodisiran is not just lowering Lp(a), it appears to be getting rid of it,” she said.

Dr. O’Donoghue said that the phase 1 results suggest lepodisiran might have a somewhat longer duration of action than other siRNA therapies studied for Lp(a) so far, but said larger trials are needed to determine whether the growing number of drugs in this class differ in ways that are clinically meaningful.

Overall, the excitement in this field is probably mostly driven by the fact that there are so many promising therapies for Lp(a) that address the target in so many unique ways. Dr. O’Donoghue cited, as an example, a gene-editing therapy called CTX320 that showed impressive effects in an animal study presented at the AHA meeting as a poster. She called the pipeline for treating Lp(a) “rich.”

Elevated Lp(a) is genetically determined, so levels do not generally change over time, said Donald Lloyd-Jones, MD, chair of the department of preventive medicine, Northwestern Medicine, Chicago.

“It is not affected by your diet. It is not affected by your exercise. What your level is will be the level you will have for the rest of your life,” he said. Generally, it is recommended to have Lp(a) measured just once to more accurately calculate cardiovascular risk, but Dr. Lloyd-Jones predicted that this lipid subfraction might be measured more frequently to verify control if a therapeutic becomes available.

Dr. Nissen agreed. Estimating that 64 million people in the United States have significantly elevated Lp(a), he expects this risk to be addressed as a specific and independent target in CV risk management when and if it becomes treatable.

Dr. Nissen reported financial relationships with Novartis, Silence Therapeutics, and Eli Lilly, which provided funding for this trial. Dr. Watson reported financial relationships with Amgen, Boehringer Ingelheim, Lilly, and Novartis. Dr. Lloyd-Jones disclosed no relevant financial relationships.

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

In an early phase multicenter clinical study, large reductions in lipoprotein(a), or Lp(a), were achieved with a well-tolerated small interfering RNA (siRNA) therapeutic, lepodisiran.

The reductions in serum Lp(a) in patients receiving lepodisiran were dose dependent but adverse events were not, said Steven E. Nissen, MD, professor of medicine at the Cleveland Clinic Lerner College of Medicine.

Rather, drug-related adverse events “were uncommon and generally similar across all lepodisiran doses and the placebo group,” reported Dr. Nissen, who pointed out that safety and tolerability were the primary endpoints and purpose of this phase 1 study.
 

Lp(a) strongly associated with CV risk

Similar to LDL cholesterol (LDL-C), elevated levels of serum Lp(a) have been associated with major adverse cardiac events (MACE). In a 2022 review article that summarized pathophysiological, observational, and genetic studies, Lp(a) was found to be implicated in vascular inflammation, atherogenesis, calcification, and thrombosis.

Furthermore, Lp(a) has been associated with residual risk of cardiovascular (CV) events even after tight control of other risk factors, including elevated LDL-C, Dr. Nissen said.

So far, no well-tolerated therapy has been found to be effective for reducing Lp(a), but siRNA is a novel and attractive approach, according to Dr. Nissen, who presented these results at the annual scientific sessions of the American Heart Association. They were also published online in JAMA.

By silencing target genes, siRNA therapies can inhibit a basic step in a given pathological process. In this case, lepodisiran silences the LPA gene to halt encoding of apolipoprotein(a), which plays a key role in Lp(a) production.

Lepodisiran is not the only treatment in development for Lp(a), noted the AHA-invited discussant Michelle L. O’Donoghue, MD, chair in cardiology, Brigham and Women’s Hospital, Boston. She mentioned several other siRNA therapies, including olpasiran that was effective in a phase 2 trial she led and published in the New England Journal of Medicine.

Drugs with different mechanisms, such as the antisense oligonucleotide pelacarsen, showed activity when tested earlier this year in a phase 1 study. No study has yet been conducted to link reductions in Lp(a) with CV event risk reduction.

The current study with lepodisiran was conducted with the participation of five clinical research sites in the United States and Singapore. Participants between the ages of 18 and 65 years were enrolled if they had a serum Lp(a) of at least 75 nmol/L (30 mg/dL), which is considered moderately elevated.

They were excluded if they had CV disease or significant risk factors, including a blood pressure greater than 160/40 mm Hg, impaired renal function (eGFR < 60 mL/min per 1.73 m²), or tobacco use (> 10 cigarettes/day).

Of 340 candidates screened, 48 were randomly assigned to one placebo or six lepodisiran groups. There were 12 participants in the placebo group and 6 in each of the lepodisiran dosing groups (4 mg, 12 mg, 32 mg, 96 mg, 304 mg, and 608 mg). All doses and placebo were administered subcutaneously one time with a planned follow-up of up to 48 weeks.
 

Safety profile is placebo-like

The single most common adverse event, shared by those randomly assigned to placebo, was injection-site reaction. There were no adverse events, including laboratory abnormalities, that were persistent and clearly different for those assigned to any dose of lepodisiran relative to placebo.

The maximum median percentage change in serum Lp(a) out to day 337 of follow-up was 5% reduction in the placebo group. In the active treatment groups, the reductions were 41% on 4 mg, 59% on 12 mg, 76% on 32 mg, 96% on 304 mg, and 97% on 608 mg.

These reductions were generally sustained for as long as therapy was maintained. Maximal reductions were reached at day 85 in the 4-mg group but were achieved by day 29 in the 605-mg group, Dr. Nissen reported. In fact, serum Lp(a) was undetectable in the 605-mg group at day 29 and remained so until day 281.

Currently, there is no practical treatment for Lp(a). The only potential exception, apheresis, is “cumbersome” to perform and must be repeated for sustained reductions. Niacin and PCSK9 inhibitors are known to provide modest reductions in Lp(a), but Dr. Nissen said they are too modest to expect a meaningful clinical benefit.
 

Lp(a) not responsive to lifestyle changes

Statins as well as all lifestyle modifications, including diet, have been shown to have “little or no effect,” Dr. Nissen said.

The safety and the evidence so far of sustained Lp(a) lowering has already led to a phase 2 trial, according to Dr. Nissen, but the more important test for the future of lepodisiran will be studies powered to confirm reductions in MACE. Lepodisiran may finally allow that hypothesis to be tested.

“I think a lot of us have been waiting a long time for evidence that we can reliably reduce Lp(a),” said Karol Watson, MD, PhD, who has a research interest in lipids and is a professor of medicine at the University of California, Los Angeles.

Although she conceded that the overwhelming evidence that Lp(a) is a risk factor does not ensure that any specific Lp(a)-lowering therapy will be clinically viable, she suggested this drug is a promising candidate to move this field forward.

“At the highest doses, lepodisiran is not just lowering Lp(a), it appears to be getting rid of it,” she said.

Dr. O’Donoghue said that the phase 1 results suggest lepodisiran might have a somewhat longer duration of action than other siRNA therapies studied for Lp(a) so far, but said larger trials are needed to determine whether the growing number of drugs in this class differ in ways that are clinically meaningful.

Overall, the excitement in this field is probably mostly driven by the fact that there are so many promising therapies for Lp(a) that address the target in so many unique ways. Dr. O’Donoghue cited, as an example, a gene-editing therapy called CTX320 that showed impressive effects in an animal study presented at the AHA meeting as a poster. She called the pipeline for treating Lp(a) “rich.”

Elevated Lp(a) is genetically determined, so levels do not generally change over time, said Donald Lloyd-Jones, MD, chair of the department of preventive medicine, Northwestern Medicine, Chicago.

“It is not affected by your diet. It is not affected by your exercise. What your level is will be the level you will have for the rest of your life,” he said. Generally, it is recommended to have Lp(a) measured just once to more accurately calculate cardiovascular risk, but Dr. Lloyd-Jones predicted that this lipid subfraction might be measured more frequently to verify control if a therapeutic becomes available.

Dr. Nissen agreed. Estimating that 64 million people in the United States have significantly elevated Lp(a), he expects this risk to be addressed as a specific and independent target in CV risk management when and if it becomes treatable.

Dr. Nissen reported financial relationships with Novartis, Silence Therapeutics, and Eli Lilly, which provided funding for this trial. Dr. Watson reported financial relationships with Amgen, Boehringer Ingelheim, Lilly, and Novartis. Dr. Lloyd-Jones disclosed no relevant financial relationships.

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

PHILADELPHIA – Percutaneous coronary intervention (PCI) in patients with stable coronary artery disease (CAD) reduces angina frequency, increases exercise capacity, and improves quality of life, results of a placebo-controlled, randomized trial show, confirming advantages that have never before been proven.

“The effect of PCI was immediate, sustained over 12 weeks, and consistent across all endpoints,” reported Christopher A. Rajkumar, MBBS, an interventional cardiology registrar at the Imperial College Healthcare Trust, London.

Results of the trial, ORBITA-2, were presented at the annual scientific sessions of the American Heart Association and simultaneously published online in the New England Journal of Medicine.

Symptom relief has long been a justification for PCI in patients with stable CAD, but the evidence has been derived from uncontrolled studies, Dr. Rajkumar said. However, the first ORBITA trial, which was also placebo controlled and randomized, failed to show benefit.

Dr. Rajkumar acknowledged that the benefit of PCI in ORBITA-2 was lower than previously reported in nonrandomized trials. He also noted that 59% of patients still had at least some angina symptoms following PCI.

Even though ORBITA-2 proves that PCI is better than no PCI, he agreed that well-informed patients, such as those who wish to avoid an invasive procedure, might still reasonably select antianginal medication over PCI. Current guidelines recommend PCI for patients with refractory angina despite medical therapy.

While Dr. Rajkumar was unwilling to speculate on how these data might change guidelines, he did say that patients with stable CAD and angina “now have a choice of two first-line evidence-based pathways.”
 

‘Remarkable’ trial

“ORBITA 2 is a rather remarkable trial because my surgical colleagues have been asking me for many decades whether PCI actually works,” said Martin B. Leon, MD, professor of medicine, Columbia University Irving Medical Center, New York. “Now I can say with confidence on the basis of a placebo-controlled trial that PCI certainly does have a favorable impact in patients with documented angina, severe coronary stenosis, and demonstrated ischemia.”

The key enrollment criteria for ORBITA-2 were angina, severe coronary stenosis in at least one vessel, and ischemia on stress imaging or invasive physiology. Unlike the previous ORBITA trial, which was limited to single-vessel disease and did not require objective evidence of ischemia, ORBITA 2 employed change in angina, rather than improved exercise capacity, as its primary endpoint.

Relative to sham PCI, patients randomly assigned to an interventional procedure had a more than twofold increase in the odds ratio of improved angina control (OR, 2.2; P < .001) based on a patient scoring system that captured angina symptoms as well as angina medication use on a smartphone application.  

The advantage of PCI over sham PCI was also significant for all secondary outcomes. These included a nearly fourfold greater (OR, 3.76; P < .001) likelihood of improvement in the Canadian Cardiovascular Society angina grade and a 1-minute increase (from 10 min. 40 seconds to 11 min. 40 seconds) in treadmill exercise time (P = .008).

On quality of life measured with the self-assessment questionnaire and the EQ-5D-5L, almost all endpoints were highly statistically significant in favor of PCI (typically on the level of P < .001).

The study had a bold design: At enrollment patients stopped all antianginal medications to undergo dobutamine echocardiography and other baseline tests. They were stopped again 2 weeks later, when patients were randomized.  

With a study protocol that enrolled patients off medication, “we intentionally diverged from the clinical guidelines,” Dr. Rajkumar said.

Of the 439 patients enrolled, 301 were randomly assigned at the end of the 2-week period, when patients were already sedated. Control patients remained sedated for at least 15 minutes. All 151 of those randomized to PCI and the 150 control patients were available for the intent-to-treat analysis at the end of 12 weeks.

The novel angina symptom burden score was created from daily angina episodes and units of daily antianginal medication captured on the smartphone app. On an ordinal scale, a score of 0 on any given day represented no anginal symptoms and no antianginal medication.

As angina severity or medication use increased, it raised the daily scores. If there was unacceptable angina (requiring the patient to be removed from the blind), acute coronary syndrome, or death, it produced the highest scores, which reached a maximum of 79.

The favorable OR for a lower symptom burden in the PCI group reflected a relative reduction in angina observed the first day after the procedure. Over the entire follow-up, more patients in the PCI group had an angina score of 0 and more of those who had angina did not take antianginal medications.

This objective evidence that PCI reduces symptoms and improves quality of life in patients with angina and stable CAD was met at the AHA late-breaking session with a sustained ovation.
 

ORBITA-2 addresses ORBITA criticisms

Connie N. Hess, MD, the AHA-invited discussant and an interventional cardiologist at the University of Colorado Medicine, Aurora, provided perspective on the differences between ORBITA 2 and ORBITA, which she said “addressed a fundamentally different hypothesis” by focusing on angina rather than exercise capacity.

Of the criticisms of the original ORBITA, which Dr. Hess noted was the first sham-controlled PCI trial ever conducted in stable CAD, one is that patients with multivessel disease were excluded, another was that objectively proven ischemia was not required, and a third was that the study of 6 weeks had a short duration.

“ORBITA 2 addressed many of these concerns,” Dr. Hess said, but, when noting that 80% of patients in the newer trial still had single vessel disease, she questioned whether the true effect of PCI for improving symptoms might still be underestimated.

ORBITA-2 was supported by the National Institute for Health and Care Research Imperial Biomedical Research Centre, the Medical Research Council, NIHR, the British Heart Foundation, Philips, and St. Mary’s Coronary Flow Trust. Dr. Rajkumar reported relevant financial relationships. Dr. Leon reported financial relationships with Abbott Vascular, Anteris, Boston Scientific, Edwards Lifesciences, Foldax, and Medtronic. Dr. Hess has financial relationships with more than 20 pharmaceutical companies, but none related specifically to this presentation.

PHILADELPHIA – Percutaneous coronary intervention (PCI) in patients with stable coronary artery disease (CAD) reduces angina frequency, increases exercise capacity, and improves quality of life, results of a placebo-controlled, randomized trial show, confirming advantages that have never before been proven.

“The effect of PCI was immediate, sustained over 12 weeks, and consistent across all endpoints,” reported Christopher A. Rajkumar, MBBS, an interventional cardiology registrar at the Imperial College Healthcare Trust, London.

Results of the trial, ORBITA-2, were presented at the annual scientific sessions of the American Heart Association and simultaneously published online in the New England Journal of Medicine.

Symptom relief has long been a justification for PCI in patients with stable CAD, but the evidence has been derived from uncontrolled studies, Dr. Rajkumar said. However, the first ORBITA trial, which was also placebo controlled and randomized, failed to show benefit.

Dr. Rajkumar acknowledged that the benefit of PCI in ORBITA-2 was lower than previously reported in nonrandomized trials. He also noted that 59% of patients still had at least some angina symptoms following PCI.

Even though ORBITA-2 proves that PCI is better than no PCI, he agreed that well-informed patients, such as those who wish to avoid an invasive procedure, might still reasonably select antianginal medication over PCI. Current guidelines recommend PCI for patients with refractory angina despite medical therapy.

While Dr. Rajkumar was unwilling to speculate on how these data might change guidelines, he did say that patients with stable CAD and angina “now have a choice of two first-line evidence-based pathways.”
 

‘Remarkable’ trial

“ORBITA 2 is a rather remarkable trial because my surgical colleagues have been asking me for many decades whether PCI actually works,” said Martin B. Leon, MD, professor of medicine, Columbia University Irving Medical Center, New York. “Now I can say with confidence on the basis of a placebo-controlled trial that PCI certainly does have a favorable impact in patients with documented angina, severe coronary stenosis, and demonstrated ischemia.”

The key enrollment criteria for ORBITA-2 were angina, severe coronary stenosis in at least one vessel, and ischemia on stress imaging or invasive physiology. Unlike the previous ORBITA trial, which was limited to single-vessel disease and did not require objective evidence of ischemia, ORBITA 2 employed change in angina, rather than improved exercise capacity, as its primary endpoint.

Relative to sham PCI, patients randomly assigned to an interventional procedure had a more than twofold increase in the odds ratio of improved angina control (OR, 2.2; P < .001) based on a patient scoring system that captured angina symptoms as well as angina medication use on a smartphone application.  

The advantage of PCI over sham PCI was also significant for all secondary outcomes. These included a nearly fourfold greater (OR, 3.76; P < .001) likelihood of improvement in the Canadian Cardiovascular Society angina grade and a 1-minute increase (from 10 min. 40 seconds to 11 min. 40 seconds) in treadmill exercise time (P = .008).

On quality of life measured with the self-assessment questionnaire and the EQ-5D-5L, almost all endpoints were highly statistically significant in favor of PCI (typically on the level of P < .001).

The study had a bold design: At enrollment patients stopped all antianginal medications to undergo dobutamine echocardiography and other baseline tests. They were stopped again 2 weeks later, when patients were randomized.  

With a study protocol that enrolled patients off medication, “we intentionally diverged from the clinical guidelines,” Dr. Rajkumar said.

Of the 439 patients enrolled, 301 were randomly assigned at the end of the 2-week period, when patients were already sedated. Control patients remained sedated for at least 15 minutes. All 151 of those randomized to PCI and the 150 control patients were available for the intent-to-treat analysis at the end of 12 weeks.

The novel angina symptom burden score was created from daily angina episodes and units of daily antianginal medication captured on the smartphone app. On an ordinal scale, a score of 0 on any given day represented no anginal symptoms and no antianginal medication.

As angina severity or medication use increased, it raised the daily scores. If there was unacceptable angina (requiring the patient to be removed from the blind), acute coronary syndrome, or death, it produced the highest scores, which reached a maximum of 79.

The favorable OR for a lower symptom burden in the PCI group reflected a relative reduction in angina observed the first day after the procedure. Over the entire follow-up, more patients in the PCI group had an angina score of 0 and more of those who had angina did not take antianginal medications.

This objective evidence that PCI reduces symptoms and improves quality of life in patients with angina and stable CAD was met at the AHA late-breaking session with a sustained ovation.
 

ORBITA-2 addresses ORBITA criticisms

Connie N. Hess, MD, the AHA-invited discussant and an interventional cardiologist at the University of Colorado Medicine, Aurora, provided perspective on the differences between ORBITA 2 and ORBITA, which she said “addressed a fundamentally different hypothesis” by focusing on angina rather than exercise capacity.

Of the criticisms of the original ORBITA, which Dr. Hess noted was the first sham-controlled PCI trial ever conducted in stable CAD, one is that patients with multivessel disease were excluded, another was that objectively proven ischemia was not required, and a third was that the study of 6 weeks had a short duration.

“ORBITA 2 addressed many of these concerns,” Dr. Hess said, but, when noting that 80% of patients in the newer trial still had single vessel disease, she questioned whether the true effect of PCI for improving symptoms might still be underestimated.

ORBITA-2 was supported by the National Institute for Health and Care Research Imperial Biomedical Research Centre, the Medical Research Council, NIHR, the British Heart Foundation, Philips, and St. Mary’s Coronary Flow Trust. Dr. Rajkumar reported relevant financial relationships. Dr. Leon reported financial relationships with Abbott Vascular, Anteris, Boston Scientific, Edwards Lifesciences, Foldax, and Medtronic. Dr. Hess has financial relationships with more than 20 pharmaceutical companies, but none related specifically to this presentation.

PHILADELPHIA – Percutaneous coronary intervention (PCI) in patients with stable coronary artery disease (CAD) reduces angina frequency, increases exercise capacity, and improves quality of life, results of a placebo-controlled, randomized trial show, confirming advantages that have never before been proven.

“The effect of PCI was immediate, sustained over 12 weeks, and consistent across all endpoints,” reported Christopher A. Rajkumar, MBBS, an interventional cardiology registrar at the Imperial College Healthcare Trust, London.

Results of the trial, ORBITA-2, were presented at the annual scientific sessions of the American Heart Association and simultaneously published online in the New England Journal of Medicine.

Symptom relief has long been a justification for PCI in patients with stable CAD, but the evidence has been derived from uncontrolled studies, Dr. Rajkumar said. However, the first ORBITA trial, which was also placebo controlled and randomized, failed to show benefit.

Dr. Rajkumar acknowledged that the benefit of PCI in ORBITA-2 was lower than previously reported in nonrandomized trials. He also noted that 59% of patients still had at least some angina symptoms following PCI.

Even though ORBITA-2 proves that PCI is better than no PCI, he agreed that well-informed patients, such as those who wish to avoid an invasive procedure, might still reasonably select antianginal medication over PCI. Current guidelines recommend PCI for patients with refractory angina despite medical therapy.

While Dr. Rajkumar was unwilling to speculate on how these data might change guidelines, he did say that patients with stable CAD and angina “now have a choice of two first-line evidence-based pathways.”
 

‘Remarkable’ trial

“ORBITA 2 is a rather remarkable trial because my surgical colleagues have been asking me for many decades whether PCI actually works,” said Martin B. Leon, MD, professor of medicine, Columbia University Irving Medical Center, New York. “Now I can say with confidence on the basis of a placebo-controlled trial that PCI certainly does have a favorable impact in patients with documented angina, severe coronary stenosis, and demonstrated ischemia.”

The key enrollment criteria for ORBITA-2 were angina, severe coronary stenosis in at least one vessel, and ischemia on stress imaging or invasive physiology. Unlike the previous ORBITA trial, which was limited to single-vessel disease and did not require objective evidence of ischemia, ORBITA 2 employed change in angina, rather than improved exercise capacity, as its primary endpoint.

Relative to sham PCI, patients randomly assigned to an interventional procedure had a more than twofold increase in the odds ratio of improved angina control (OR, 2.2; P < .001) based on a patient scoring system that captured angina symptoms as well as angina medication use on a smartphone application.  

The advantage of PCI over sham PCI was also significant for all secondary outcomes. These included a nearly fourfold greater (OR, 3.76; P < .001) likelihood of improvement in the Canadian Cardiovascular Society angina grade and a 1-minute increase (from 10 min. 40 seconds to 11 min. 40 seconds) in treadmill exercise time (P = .008).

On quality of life measured with the self-assessment questionnaire and the EQ-5D-5L, almost all endpoints were highly statistically significant in favor of PCI (typically on the level of P < .001).

The study had a bold design: At enrollment patients stopped all antianginal medications to undergo dobutamine echocardiography and other baseline tests. They were stopped again 2 weeks later, when patients were randomized.  

With a study protocol that enrolled patients off medication, “we intentionally diverged from the clinical guidelines,” Dr. Rajkumar said.

Of the 439 patients enrolled, 301 were randomly assigned at the end of the 2-week period, when patients were already sedated. Control patients remained sedated for at least 15 minutes. All 151 of those randomized to PCI and the 150 control patients were available for the intent-to-treat analysis at the end of 12 weeks.

The novel angina symptom burden score was created from daily angina episodes and units of daily antianginal medication captured on the smartphone app. On an ordinal scale, a score of 0 on any given day represented no anginal symptoms and no antianginal medication.

As angina severity or medication use increased, it raised the daily scores. If there was unacceptable angina (requiring the patient to be removed from the blind), acute coronary syndrome, or death, it produced the highest scores, which reached a maximum of 79.

The favorable OR for a lower symptom burden in the PCI group reflected a relative reduction in angina observed the first day after the procedure. Over the entire follow-up, more patients in the PCI group had an angina score of 0 and more of those who had angina did not take antianginal medications.

This objective evidence that PCI reduces symptoms and improves quality of life in patients with angina and stable CAD was met at the AHA late-breaking session with a sustained ovation.
 

ORBITA-2 addresses ORBITA criticisms

Connie N. Hess, MD, the AHA-invited discussant and an interventional cardiologist at the University of Colorado Medicine, Aurora, provided perspective on the differences between ORBITA 2 and ORBITA, which she said “addressed a fundamentally different hypothesis” by focusing on angina rather than exercise capacity.

Of the criticisms of the original ORBITA, which Dr. Hess noted was the first sham-controlled PCI trial ever conducted in stable CAD, one is that patients with multivessel disease were excluded, another was that objectively proven ischemia was not required, and a third was that the study of 6 weeks had a short duration.

“ORBITA 2 addressed many of these concerns,” Dr. Hess said, but, when noting that 80% of patients in the newer trial still had single vessel disease, she questioned whether the true effect of PCI for improving symptoms might still be underestimated.

ORBITA-2 was supported by the National Institute for Health and Care Research Imperial Biomedical Research Centre, the Medical Research Council, NIHR, the British Heart Foundation, Philips, and St. Mary’s Coronary Flow Trust. Dr. Rajkumar reported relevant financial relationships. Dr. Leon reported financial relationships with Abbott Vascular, Anteris, Boston Scientific, Edwards Lifesciences, Foldax, and Medtronic. Dr. Hess has financial relationships with more than 20 pharmaceutical companies, but none related specifically to this presentation.

NEW YORK – As a result of recent progress in the control of prurigo nodularis, failure to recognize the differences in presentation across skin types threatens prolonged but preventable morbidity from a disease with a devastating clinical impact, according to an expert evaluating current approaches at the Skin of Color Update 2023.

“As dermatologists, prurigo nodularis is one of the most severe diseases we treat, said Shawn G. Kwatra, MD, director of the Johns Hopkins Itch Center, Baltimore. Now with one approved therapy and more coming, “it offers one of the most important opportunities we have to dramatically improve someone’s entire life.”

Ted Bosworth/MDedge News

Prior to the September 2022 approval of dupilumab for the treatment of prurigo nodularis (the first treatment approved for this indication), Dr. Kwatra said that the limited options for control of pruritus made him anxious. Prurigo nodularis is characterized by highly itchy nodules that can produce symptoms patients describe as unbearable.
 

Itch typically severe

On a scale for which 10 represents the worst itch imaginable, scores of 8 or greater are not unusual, according to Dr. Kwatra. Nodules on the trunk and the extensor surfaces of the arms and legs are characteristic, but the persistent itch is the immediate target of treatment once the diagnosis is made. For that reason, he urged clinicians to be familiar with the presentation in patients with darker skin types to reduce time to treatment.

In addition to the difficulty of seeing the characteristic red that is typical of erythema in lighter skin, patients with darker skin types tend to have larger nodules that might vary in shape relative to lighter skin types, Dr. Kwatra said. Given that the presentation of prurigo nodularis is highly heterogeneous even among the same skin types, the nuances in patients with darker skin can be that much more confusing for those without prior experience.

Among Blacks in particular, the nodules in some cases “can be huge,” he added. “They can almost look like keloids due to their thickened and fibrotic appearance.”
 

Phenotypes appear to be racially linked

In Black patients, the appearance can vary enough relative to lighter skin individuals, that “there seems to be something a little bit different going on,” he said, and this is, in fact, supported by a cluster analysis of circulating biomarkers reported by Dr. Kwatra and colleagues in 2022, in the Journal of Investigative Dermatology.

In that study, the biomarker profile distinguished two distinct groups. Whites were more common in a cluster with relatively low expression of inflammatory markers (cluster 1), while Blacks were more common in a cluster with an inflammatory plasma profile (cluster 2), with higher relative expression of multiple cytokines, C-reactive protein, eosinophils, and other markers of up-regulated inflammation.

In addition to a lower rate of myelopathy in cluster 2 than cluster 1 (18% vs. 67%; P = .028), patients in cluster 2 had a significantly worse itch than those in cluster 1 on the Numeric Rating Scale for itch and a significantly lower quality of life based on the Dermatology Life Quality Index score.

Other work at Dr. Kwatra’s center that is based on genetic sequencing has provided evidence that Blacks – and Asians to a lesser extent – are predisposed genetically to develop nodules, perhaps explaining why the nodules tend to be larger than those seen in Whites.

The significance of the evidence that prurigo nodularis is associated with a more up-regulated inflammatory profile in Blacks than in Whites is that they might be particularly likely to respond to dupilumab or other targeted immunomodulating therapies that are in development, according to Dr. Kwatra. Although he did not provide data on response by race, he did provide several case examples of complete itch control following dupilumab therapy in Black patients.

In his experience, high levels of blood eosinophils and other inflammatory markers are predictors of response to dupilumab regardless of skin type, but he expressed concern that time to diagnosis is sometimes longer in Black patients if the nuances of disease expression are not appreciated.

For treating prurigo nodularis in Blacks as well as Whites, Dr. Kwatra suggested that clinicians stay current with what he predicted will be a growing array of treatment options. He did not discuss nemolizumab, an interleukin-31 receptor alpha antagonist. Soon after the meeting, results of a phase 3 trial of nemolizumab in patients with moderate to severe prurigo nodularis were published in the New England Journal of Medicine. (Dr. Kwatra is the lead author of the study but did not specifically discuss this treatment at the meeting.)

In the international placebo-controlled trial, called OLYMPIA 2, treatment was associated with a significant reduction in the signs and symptoms of prurigo nodularis, including reductions in itch, at 16 weeks, although only 4% of patients in the study were Black.

Given the expanding array of therapies, the message of considering prurigo nodularis in Black patients in order to accelerate the time to diagnosis is timely, Andrew F. Alexis, MD, MPH, professor of clinical dermatology and vice-chair for diversity and inclusion for the department of dermatology, Weill Cornell Medicine, New York.

“Current studies suggest a higher prevalence and greater severity of prurigo nodularis among Black patients compared to White patients,” said Dr. Alexis, agreeing with Dr. Kwatra. Referring to evidence that Blacks might mount a greater inflammatory response to prurigo nodularis than Whites, Dr. Alexis called for “a better understanding of the pathomechanisms” of this disease in order “to address unmet needs and reduce disparities for our diverse population of patients who suffer from prurigo nodularis.’

Dr. Kwatra reported financial relationships with AbbVie, Amgen, Arcutis, ASLAN, Cara, Castle Biosciences, Celldex, Galderma, Incyte, Johnson & Johnson, LEO pharma, Novartis, Pfizer, Regeneron, and Sanofi.

NEW YORK – As a result of recent progress in the control of prurigo nodularis, failure to recognize the differences in presentation across skin types threatens prolonged but preventable morbidity from a disease with a devastating clinical impact, according to an expert evaluating current approaches at the Skin of Color Update 2023.

“As dermatologists, prurigo nodularis is one of the most severe diseases we treat, said Shawn G. Kwatra, MD, director of the Johns Hopkins Itch Center, Baltimore. Now with one approved therapy and more coming, “it offers one of the most important opportunities we have to dramatically improve someone’s entire life.”

Ted Bosworth/MDedge News

Prior to the September 2022 approval of dupilumab for the treatment of prurigo nodularis (the first treatment approved for this indication), Dr. Kwatra said that the limited options for control of pruritus made him anxious. Prurigo nodularis is characterized by highly itchy nodules that can produce symptoms patients describe as unbearable.
 

Itch typically severe

On a scale for which 10 represents the worst itch imaginable, scores of 8 or greater are not unusual, according to Dr. Kwatra. Nodules on the trunk and the extensor surfaces of the arms and legs are characteristic, but the persistent itch is the immediate target of treatment once the diagnosis is made. For that reason, he urged clinicians to be familiar with the presentation in patients with darker skin types to reduce time to treatment.

In addition to the difficulty of seeing the characteristic red that is typical of erythema in lighter skin, patients with darker skin types tend to have larger nodules that might vary in shape relative to lighter skin types, Dr. Kwatra said. Given that the presentation of prurigo nodularis is highly heterogeneous even among the same skin types, the nuances in patients with darker skin can be that much more confusing for those without prior experience.

Among Blacks in particular, the nodules in some cases “can be huge,” he added. “They can almost look like keloids due to their thickened and fibrotic appearance.”
 

Phenotypes appear to be racially linked

In Black patients, the appearance can vary enough relative to lighter skin individuals, that “there seems to be something a little bit different going on,” he said, and this is, in fact, supported by a cluster analysis of circulating biomarkers reported by Dr. Kwatra and colleagues in 2022, in the Journal of Investigative Dermatology.

In that study, the biomarker profile distinguished two distinct groups. Whites were more common in a cluster with relatively low expression of inflammatory markers (cluster 1), while Blacks were more common in a cluster with an inflammatory plasma profile (cluster 2), with higher relative expression of multiple cytokines, C-reactive protein, eosinophils, and other markers of up-regulated inflammation.

In addition to a lower rate of myelopathy in cluster 2 than cluster 1 (18% vs. 67%; P = .028), patients in cluster 2 had a significantly worse itch than those in cluster 1 on the Numeric Rating Scale for itch and a significantly lower quality of life based on the Dermatology Life Quality Index score.

Other work at Dr. Kwatra’s center that is based on genetic sequencing has provided evidence that Blacks – and Asians to a lesser extent – are predisposed genetically to develop nodules, perhaps explaining why the nodules tend to be larger than those seen in Whites.

The significance of the evidence that prurigo nodularis is associated with a more up-regulated inflammatory profile in Blacks than in Whites is that they might be particularly likely to respond to dupilumab or other targeted immunomodulating therapies that are in development, according to Dr. Kwatra. Although he did not provide data on response by race, he did provide several case examples of complete itch control following dupilumab therapy in Black patients.

In his experience, high levels of blood eosinophils and other inflammatory markers are predictors of response to dupilumab regardless of skin type, but he expressed concern that time to diagnosis is sometimes longer in Black patients if the nuances of disease expression are not appreciated.

For treating prurigo nodularis in Blacks as well as Whites, Dr. Kwatra suggested that clinicians stay current with what he predicted will be a growing array of treatment options. He did not discuss nemolizumab, an interleukin-31 receptor alpha antagonist. Soon after the meeting, results of a phase 3 trial of nemolizumab in patients with moderate to severe prurigo nodularis were published in the New England Journal of Medicine. (Dr. Kwatra is the lead author of the study but did not specifically discuss this treatment at the meeting.)

In the international placebo-controlled trial, called OLYMPIA 2, treatment was associated with a significant reduction in the signs and symptoms of prurigo nodularis, including reductions in itch, at 16 weeks, although only 4% of patients in the study were Black.

Given the expanding array of therapies, the message of considering prurigo nodularis in Black patients in order to accelerate the time to diagnosis is timely, Andrew F. Alexis, MD, MPH, professor of clinical dermatology and vice-chair for diversity and inclusion for the department of dermatology, Weill Cornell Medicine, New York.

“Current studies suggest a higher prevalence and greater severity of prurigo nodularis among Black patients compared to White patients,” said Dr. Alexis, agreeing with Dr. Kwatra. Referring to evidence that Blacks might mount a greater inflammatory response to prurigo nodularis than Whites, Dr. Alexis called for “a better understanding of the pathomechanisms” of this disease in order “to address unmet needs and reduce disparities for our diverse population of patients who suffer from prurigo nodularis.’

Dr. Kwatra reported financial relationships with AbbVie, Amgen, Arcutis, ASLAN, Cara, Castle Biosciences, Celldex, Galderma, Incyte, Johnson & Johnson, LEO pharma, Novartis, Pfizer, Regeneron, and Sanofi.

NEW YORK – As a result of recent progress in the control of prurigo nodularis, failure to recognize the differences in presentation across skin types threatens prolonged but preventable morbidity from a disease with a devastating clinical impact, according to an expert evaluating current approaches at the Skin of Color Update 2023.

“As dermatologists, prurigo nodularis is one of the most severe diseases we treat, said Shawn G. Kwatra, MD, director of the Johns Hopkins Itch Center, Baltimore. Now with one approved therapy and more coming, “it offers one of the most important opportunities we have to dramatically improve someone’s entire life.”

Ted Bosworth/MDedge News

Prior to the September 2022 approval of dupilumab for the treatment of prurigo nodularis (the first treatment approved for this indication), Dr. Kwatra said that the limited options for control of pruritus made him anxious. Prurigo nodularis is characterized by highly itchy nodules that can produce symptoms patients describe as unbearable.
 

Itch typically severe

On a scale for which 10 represents the worst itch imaginable, scores of 8 or greater are not unusual, according to Dr. Kwatra. Nodules on the trunk and the extensor surfaces of the arms and legs are characteristic, but the persistent itch is the immediate target of treatment once the diagnosis is made. For that reason, he urged clinicians to be familiar with the presentation in patients with darker skin types to reduce time to treatment.

In addition to the difficulty of seeing the characteristic red that is typical of erythema in lighter skin, patients with darker skin types tend to have larger nodules that might vary in shape relative to lighter skin types, Dr. Kwatra said. Given that the presentation of prurigo nodularis is highly heterogeneous even among the same skin types, the nuances in patients with darker skin can be that much more confusing for those without prior experience.

Among Blacks in particular, the nodules in some cases “can be huge,” he added. “They can almost look like keloids due to their thickened and fibrotic appearance.”
 

Phenotypes appear to be racially linked

In Black patients, the appearance can vary enough relative to lighter skin individuals, that “there seems to be something a little bit different going on,” he said, and this is, in fact, supported by a cluster analysis of circulating biomarkers reported by Dr. Kwatra and colleagues in 2022, in the Journal of Investigative Dermatology.

In that study, the biomarker profile distinguished two distinct groups. Whites were more common in a cluster with relatively low expression of inflammatory markers (cluster 1), while Blacks were more common in a cluster with an inflammatory plasma profile (cluster 2), with higher relative expression of multiple cytokines, C-reactive protein, eosinophils, and other markers of up-regulated inflammation.

In addition to a lower rate of myelopathy in cluster 2 than cluster 1 (18% vs. 67%; P = .028), patients in cluster 2 had a significantly worse itch than those in cluster 1 on the Numeric Rating Scale for itch and a significantly lower quality of life based on the Dermatology Life Quality Index score.

Other work at Dr. Kwatra’s center that is based on genetic sequencing has provided evidence that Blacks – and Asians to a lesser extent – are predisposed genetically to develop nodules, perhaps explaining why the nodules tend to be larger than those seen in Whites.

The significance of the evidence that prurigo nodularis is associated with a more up-regulated inflammatory profile in Blacks than in Whites is that they might be particularly likely to respond to dupilumab or other targeted immunomodulating therapies that are in development, according to Dr. Kwatra. Although he did not provide data on response by race, he did provide several case examples of complete itch control following dupilumab therapy in Black patients.

In his experience, high levels of blood eosinophils and other inflammatory markers are predictors of response to dupilumab regardless of skin type, but he expressed concern that time to diagnosis is sometimes longer in Black patients if the nuances of disease expression are not appreciated.

For treating prurigo nodularis in Blacks as well as Whites, Dr. Kwatra suggested that clinicians stay current with what he predicted will be a growing array of treatment options. He did not discuss nemolizumab, an interleukin-31 receptor alpha antagonist. Soon after the meeting, results of a phase 3 trial of nemolizumab in patients with moderate to severe prurigo nodularis were published in the New England Journal of Medicine. (Dr. Kwatra is the lead author of the study but did not specifically discuss this treatment at the meeting.)

In the international placebo-controlled trial, called OLYMPIA 2, treatment was associated with a significant reduction in the signs and symptoms of prurigo nodularis, including reductions in itch, at 16 weeks, although only 4% of patients in the study were Black.

Given the expanding array of therapies, the message of considering prurigo nodularis in Black patients in order to accelerate the time to diagnosis is timely, Andrew F. Alexis, MD, MPH, professor of clinical dermatology and vice-chair for diversity and inclusion for the department of dermatology, Weill Cornell Medicine, New York.

“Current studies suggest a higher prevalence and greater severity of prurigo nodularis among Black patients compared to White patients,” said Dr. Alexis, agreeing with Dr. Kwatra. Referring to evidence that Blacks might mount a greater inflammatory response to prurigo nodularis than Whites, Dr. Alexis called for “a better understanding of the pathomechanisms” of this disease in order “to address unmet needs and reduce disparities for our diverse population of patients who suffer from prurigo nodularis.’

Dr. Kwatra reported financial relationships with AbbVie, Amgen, Arcutis, ASLAN, Cara, Castle Biosciences, Celldex, Galderma, Incyte, Johnson & Johnson, LEO pharma, Novartis, Pfizer, Regeneron, and Sanofi.

BERLIN – European guidelines now in press for the diagnosis and treatment of body dysmorphic disorder (BDD), a condition defined largely by abnormal perceptions about – and behavior surrounding personal appearance, were outlined in a late-breaker presentation at the annual Congress of the European Academy of Dermatology and Venereology.

The development of guidelines for BDD, a disorder familiar to many clinical dermatologists, is intended as a practical tool, according to Maria-Angeliki Gkini, MD, who has appointments at both Bart’s Health NHS Trust in London and the 401 General Army Hospital in Athens.

Consensus reached by 17 experts

Specifically, 17 experts, all of whom were members of the European Society for Dermatology and Psychiatry proceeded to systematically address a series of clinical questions and recommendations. Consensus was defined as at least 75% of the participants strongly agreeing or agreeing. Several rounds of discussion were often required.

Among the conclusions, the guidelines support uniform screening for BDD in all patients prior to cosmetic procedures. In identifying depression, anxiety, and distorted perceptions, simple tools, such as the Patient Health Questionnaire might be adequate for an initial evaluation, but Dr. Gkini also recommended routinely inquiring about suicidal ideation, which has been reported in up to 80% of individuals with BDD.

Other instruments for screening that can be considered include DSM-5 criteria for BDD and the Body Dysmorphic Disorder Questionnaire–Dermatology Version, which might be particularly useful and appropriate for dermatologists.

One of the reasons to screen for BDD is that these patients often convince themselves that some specific procedure is needed to resolve the source of their obsession. The goal of screening is to verify that it is the dermatologic concern, not an underlying psychiatric disorder that is driving their search for relief. The risk of dermatologic interventions is not only that expectations are not met, but the patient’s perception of a failed intervention “sometimes makes these worse,” Dr. Gkini explained.
 

Collaboration with psychiatrists recommended

The guidelines include suggestions for treatment of BDD. Of these, SSRIs are recommended at high relative doses, according to Dr. Gkini. Consistent with the consensus recommendation of collaborating with mental health specialists, she said that the recommendations acknowledge evidence of greater benefits when SSRIs are combined with psychotherapy.

Katharine A. Phillips, MD, professor of psychiatry at Weill Cornell Medicine, New York, has been conducting BDD research for several years and has written numerous books and articles about this topic, including a review in the journal Focus. She cautioned that, because of a normal concern for appearance, BDD is easily missed by dermatologists.

“For BDD to be diagnosed, the preoccupation with a nonexistent or slight defect in appearance must cause clinically significant distress or impairment in functioning,” she said in an interview. “This is necessary to differentiate BDD from more normal and common appearance concerns that do not qualify for the diagnosis”

She specified that patients should be considered for cognitive-behavioral therapy rather than psychotherapy, a generic term that covers many forms of treatment. She said that most other types of psychotherapy “are probably not effective” for BDD.

Dr. Phillips highly endorsed the development of BDD guidelines for dermatologists because of the frequency with which physicians in this specialty encounter BDD – and believes that more attention to this diagnosis is needed.

“I recommend that dermatologists who have a patient with BDD collaborate with a psychiatrist in delivering care with an SSRI,” she said. “High doses of these medications are often needed to effectively treat BDD.”

Dr. Gkini reported financial relationships with AbbVie, Almirall, Celgene, Eli Lilly, Janssen, LEO, Novartis, Sanofi, and Regenlab. Dr. Phillips reported no relevant financial relationships.

BERLIN – European guidelines now in press for the diagnosis and treatment of body dysmorphic disorder (BDD), a condition defined largely by abnormal perceptions about – and behavior surrounding personal appearance, were outlined in a late-breaker presentation at the annual Congress of the European Academy of Dermatology and Venereology.

The development of guidelines for BDD, a disorder familiar to many clinical dermatologists, is intended as a practical tool, according to Maria-Angeliki Gkini, MD, who has appointments at both Bart’s Health NHS Trust in London and the 401 General Army Hospital in Athens.

Consensus reached by 17 experts

Specifically, 17 experts, all of whom were members of the European Society for Dermatology and Psychiatry proceeded to systematically address a series of clinical questions and recommendations. Consensus was defined as at least 75% of the participants strongly agreeing or agreeing. Several rounds of discussion were often required.

Among the conclusions, the guidelines support uniform screening for BDD in all patients prior to cosmetic procedures. In identifying depression, anxiety, and distorted perceptions, simple tools, such as the Patient Health Questionnaire might be adequate for an initial evaluation, but Dr. Gkini also recommended routinely inquiring about suicidal ideation, which has been reported in up to 80% of individuals with BDD.

Other instruments for screening that can be considered include DSM-5 criteria for BDD and the Body Dysmorphic Disorder Questionnaire–Dermatology Version, which might be particularly useful and appropriate for dermatologists.

One of the reasons to screen for BDD is that these patients often convince themselves that some specific procedure is needed to resolve the source of their obsession. The goal of screening is to verify that it is the dermatologic concern, not an underlying psychiatric disorder that is driving their search for relief. The risk of dermatologic interventions is not only that expectations are not met, but the patient’s perception of a failed intervention “sometimes makes these worse,” Dr. Gkini explained.
 

Collaboration with psychiatrists recommended

The guidelines include suggestions for treatment of BDD. Of these, SSRIs are recommended at high relative doses, according to Dr. Gkini. Consistent with the consensus recommendation of collaborating with mental health specialists, she said that the recommendations acknowledge evidence of greater benefits when SSRIs are combined with psychotherapy.

Katharine A. Phillips, MD, professor of psychiatry at Weill Cornell Medicine, New York, has been conducting BDD research for several years and has written numerous books and articles about this topic, including a review in the journal Focus. She cautioned that, because of a normal concern for appearance, BDD is easily missed by dermatologists.

“For BDD to be diagnosed, the preoccupation with a nonexistent or slight defect in appearance must cause clinically significant distress or impairment in functioning,” she said in an interview. “This is necessary to differentiate BDD from more normal and common appearance concerns that do not qualify for the diagnosis”

She specified that patients should be considered for cognitive-behavioral therapy rather than psychotherapy, a generic term that covers many forms of treatment. She said that most other types of psychotherapy “are probably not effective” for BDD.

Dr. Phillips highly endorsed the development of BDD guidelines for dermatologists because of the frequency with which physicians in this specialty encounter BDD – and believes that more attention to this diagnosis is needed.

“I recommend that dermatologists who have a patient with BDD collaborate with a psychiatrist in delivering care with an SSRI,” she said. “High doses of these medications are often needed to effectively treat BDD.”

Dr. Gkini reported financial relationships with AbbVie, Almirall, Celgene, Eli Lilly, Janssen, LEO, Novartis, Sanofi, and Regenlab. Dr. Phillips reported no relevant financial relationships.

BERLIN – European guidelines now in press for the diagnosis and treatment of body dysmorphic disorder (BDD), a condition defined largely by abnormal perceptions about – and behavior surrounding personal appearance, were outlined in a late-breaker presentation at the annual Congress of the European Academy of Dermatology and Venereology.

The development of guidelines for BDD, a disorder familiar to many clinical dermatologists, is intended as a practical tool, according to Maria-Angeliki Gkini, MD, who has appointments at both Bart’s Health NHS Trust in London and the 401 General Army Hospital in Athens.

Consensus reached by 17 experts

Specifically, 17 experts, all of whom were members of the European Society for Dermatology and Psychiatry proceeded to systematically address a series of clinical questions and recommendations. Consensus was defined as at least 75% of the participants strongly agreeing or agreeing. Several rounds of discussion were often required.

Among the conclusions, the guidelines support uniform screening for BDD in all patients prior to cosmetic procedures. In identifying depression, anxiety, and distorted perceptions, simple tools, such as the Patient Health Questionnaire might be adequate for an initial evaluation, but Dr. Gkini also recommended routinely inquiring about suicidal ideation, which has been reported in up to 80% of individuals with BDD.

Other instruments for screening that can be considered include DSM-5 criteria for BDD and the Body Dysmorphic Disorder Questionnaire–Dermatology Version, which might be particularly useful and appropriate for dermatologists.

One of the reasons to screen for BDD is that these patients often convince themselves that some specific procedure is needed to resolve the source of their obsession. The goal of screening is to verify that it is the dermatologic concern, not an underlying psychiatric disorder that is driving their search for relief. The risk of dermatologic interventions is not only that expectations are not met, but the patient’s perception of a failed intervention “sometimes makes these worse,” Dr. Gkini explained.
 

Collaboration with psychiatrists recommended

The guidelines include suggestions for treatment of BDD. Of these, SSRIs are recommended at high relative doses, according to Dr. Gkini. Consistent with the consensus recommendation of collaborating with mental health specialists, she said that the recommendations acknowledge evidence of greater benefits when SSRIs are combined with psychotherapy.

Katharine A. Phillips, MD, professor of psychiatry at Weill Cornell Medicine, New York, has been conducting BDD research for several years and has written numerous books and articles about this topic, including a review in the journal Focus. She cautioned that, because of a normal concern for appearance, BDD is easily missed by dermatologists.

“For BDD to be diagnosed, the preoccupation with a nonexistent or slight defect in appearance must cause clinically significant distress or impairment in functioning,” she said in an interview. “This is necessary to differentiate BDD from more normal and common appearance concerns that do not qualify for the diagnosis”

She specified that patients should be considered for cognitive-behavioral therapy rather than psychotherapy, a generic term that covers many forms of treatment. She said that most other types of psychotherapy “are probably not effective” for BDD.

Dr. Phillips highly endorsed the development of BDD guidelines for dermatologists because of the frequency with which physicians in this specialty encounter BDD – and believes that more attention to this diagnosis is needed.

“I recommend that dermatologists who have a patient with BDD collaborate with a psychiatrist in delivering care with an SSRI,” she said. “High doses of these medications are often needed to effectively treat BDD.”

Dr. Gkini reported financial relationships with AbbVie, Almirall, Celgene, Eli Lilly, Janssen, LEO, Novartis, Sanofi, and Regenlab. Dr. Phillips reported no relevant financial relationships.

BERLIN – Based on a phase 3 trial, treatment with the topical Janus kinase (JAK) inhibitor ruxolitinib appears to be as safe and effective for the control of atopic dermatitis (AD) in children aged 2-11 years as previously shown in adolescents and adults for whom it already has an approved indication.

In this study – TRUE-AD3 – systemic exposure to ruxolitinib, which is selective for JAK1 and 2, was followed closely, and the low mean plasma concentrations “suggest systemic JAK inhibition is highly unlikely,” Lawrence F. Eichenfield, MD, professor of dermatology and pediatrics at the University of California, San Diego, said at the annual congress of the European Academy of Dermatology and Venereology.

Ted Bosworth/MDedge News

For example, at a plasma concentration no greater than 27 nM in both younger and older patients at 4 weeks and again at 8 weeks, the systemic exposure was about a tenth of that (281 nM) previously associated with myelosuppression, he reported.

Given the boxed warning for oral JAK inhibitors, which was based largely on a 2022 study in adults with rheumatoid arthritis that associated tofacitinib, a nonspecific JAK inhibitor, with an increased risk of thrombotic events in adults already at risk for these events, safety was a focus of this phase 3 trial. The boxed warning is also in the labeling for topical ruxolitinib, 1.5% (Opzelura), approved for treating to mild to moderate atopic dermatitis in patients 12 years of age and older.

Dr. Eichenfield said there were no significant safety signals in the younger pediatric population. “There were no treatment-emergent adverse events suggestive of systemic JAK inhibition,” he said. This not only included the absence of serious infections, cardiac events, thromboses, or malignancies, but there was no signal of hematologic abnormalities, such as change in hemoglobin or neutrophil count.
 

Application site reactions

Rather, in the study of children ages 2-11, the only adverse events associated with topical ruxolitinib not observed in the control arm, which received the vehicle alone, were application site reactions, such as pain, erythema, and irritation. None of these occurred in more than 3% of those randomized to ruxolitinib regardless of dose.

Overall, in the trial, which randomized 329 patients ages from 2 to under 12 years with mild to moderate AD to ruxolitinib 1.5% cream, ruxolitinib 0.75% cream, or vehicle in a 2:2:1 fashion, there were just two (0.8%) discontinuations in the ruxolitinib groups (one in each dosing arm). There were none in the vehicle arm.

The safety supports an expansion of the AD indication for topical ruxolitinib in young children, because the rates of response were very similar to that seen in adolescents and adults in the previously published TRUE AD-1 and TRUE AD-2 trials, he said.

For the primary endpoint of Investigator’s Global Assessment (IGA) score of 0 (clear) or 1 (almost clear) with at least a 2 grade improvement in IGA score from baseline, the response rates were 56.5%, 36.6%, and 10.8% for ruxolitinib 1.5%, ruxolitinib 0.75%, and vehicle respectively, at 8 weeks (P < .0001 for both doses relative to vehicle).

For the secondary efficacy endpoint of 75% or greater clearance on the Eczema Area and Severity Index, the rates were 67.2%, 51.5%, and 15.4%, for ruxolitinib 1.5%, ruxolitinib 0.75%, and vehicle respectively. Again, the advantage of both doses of ruxolitinib relative to vehicle was highly statistically significant (P < .0001).

Control of itch, evaluated with the Numerical Rating Scale was only evaluated in children 6-2 because of concern of the reliability of reporting in younger children. Control was defined as at least a 4-point improvement from baseline. It was achieved by 43.4%, 37.5%, and 29.7% by week 8 in the arms receiving the higher dose of ruxolitinib, the lower dose, and vehicle, respectively. The median time to achieving itch control was 11 days, 13 days, and 23 days, respectively. For all of these endpoints, the separation of the curves was readily apparent within the first 2 weeks.

The efficacy and tolerability of ruxolitinib appeared to be similar in younger children (ages 2-6) relative to older children.
 

Extension study in children near completion

Most of the patients who participated in TRUE AD-3 have been rolled over to the open-label extension trial, which is nearing completion. Those originally randomized to vehicle have been rerandomized to the lower or higher dose of ruxolitinib.

While this trial was focused on ruxolitinib as monotherapy, Thrasyvoulos Tzellos, MD, head of the department of dermatology, Nordland Hospital Trust, Bødo, Norway, questioned whether this is will be how it will be used in clinical practice. With the increasing array of therapies for AD, the “concept of combination therapy becomes more and more relevant,” he said after Dr. Eichenfield’s presentation.

Questioning whether an effective nonsteroidal anti-inflammatory agent like ruxolitinib should be considered a first-line treatment in mild disease or an adjunctive treatment for AD of any severity, he suggested that it might be best considered within a combination.

Dr. Eichenfield agreed. “Once we get the drug approved in a controlled trial, I think we then figure out how to use it in clinical practice.” Based on his own use of ruxolitinib in adults, he noted that he has not seen this drug replace other therapies so much as provide another option for control.

“We have an increasing armamentarium of drugs to use for involvement in different areas of the body in order to get more long-term control of disease,” he said. As an effective topical nonsteroidal drug, he believes its addition to clinical care in younger children, if approved, will be meaningful.

Dr. Eichenfield disclosed financial relationships with more multiple pharmaceutical companies, including Incyte, the manufacturer of ruxolitinib cream that provided funding for the True-AD trials. Dr. Tzellos reported financial relationships with AbbVie and UCB.

BERLIN – Based on a phase 3 trial, treatment with the topical Janus kinase (JAK) inhibitor ruxolitinib appears to be as safe and effective for the control of atopic dermatitis (AD) in children aged 2-11 years as previously shown in adolescents and adults for whom it already has an approved indication.

In this study – TRUE-AD3 – systemic exposure to ruxolitinib, which is selective for JAK1 and 2, was followed closely, and the low mean plasma concentrations “suggest systemic JAK inhibition is highly unlikely,” Lawrence F. Eichenfield, MD, professor of dermatology and pediatrics at the University of California, San Diego, said at the annual congress of the European Academy of Dermatology and Venereology.

Ted Bosworth/MDedge News

For example, at a plasma concentration no greater than 27 nM in both younger and older patients at 4 weeks and again at 8 weeks, the systemic exposure was about a tenth of that (281 nM) previously associated with myelosuppression, he reported.

Given the boxed warning for oral JAK inhibitors, which was based largely on a 2022 study in adults with rheumatoid arthritis that associated tofacitinib, a nonspecific JAK inhibitor, with an increased risk of thrombotic events in adults already at risk for these events, safety was a focus of this phase 3 trial. The boxed warning is also in the labeling for topical ruxolitinib, 1.5% (Opzelura), approved for treating to mild to moderate atopic dermatitis in patients 12 years of age and older.

Dr. Eichenfield said there were no significant safety signals in the younger pediatric population. “There were no treatment-emergent adverse events suggestive of systemic JAK inhibition,” he said. This not only included the absence of serious infections, cardiac events, thromboses, or malignancies, but there was no signal of hematologic abnormalities, such as change in hemoglobin or neutrophil count.
 

Application site reactions

Rather, in the study of children ages 2-11, the only adverse events associated with topical ruxolitinib not observed in the control arm, which received the vehicle alone, were application site reactions, such as pain, erythema, and irritation. None of these occurred in more than 3% of those randomized to ruxolitinib regardless of dose.

Overall, in the trial, which randomized 329 patients ages from 2 to under 12 years with mild to moderate AD to ruxolitinib 1.5% cream, ruxolitinib 0.75% cream, or vehicle in a 2:2:1 fashion, there were just two (0.8%) discontinuations in the ruxolitinib groups (one in each dosing arm). There were none in the vehicle arm.

The safety supports an expansion of the AD indication for topical ruxolitinib in young children, because the rates of response were very similar to that seen in adolescents and adults in the previously published TRUE AD-1 and TRUE AD-2 trials, he said.

For the primary endpoint of Investigator’s Global Assessment (IGA) score of 0 (clear) or 1 (almost clear) with at least a 2 grade improvement in IGA score from baseline, the response rates were 56.5%, 36.6%, and 10.8% for ruxolitinib 1.5%, ruxolitinib 0.75%, and vehicle respectively, at 8 weeks (P < .0001 for both doses relative to vehicle).

For the secondary efficacy endpoint of 75% or greater clearance on the Eczema Area and Severity Index, the rates were 67.2%, 51.5%, and 15.4%, for ruxolitinib 1.5%, ruxolitinib 0.75%, and vehicle respectively. Again, the advantage of both doses of ruxolitinib relative to vehicle was highly statistically significant (P < .0001).

Control of itch, evaluated with the Numerical Rating Scale was only evaluated in children 6-2 because of concern of the reliability of reporting in younger children. Control was defined as at least a 4-point improvement from baseline. It was achieved by 43.4%, 37.5%, and 29.7% by week 8 in the arms receiving the higher dose of ruxolitinib, the lower dose, and vehicle, respectively. The median time to achieving itch control was 11 days, 13 days, and 23 days, respectively. For all of these endpoints, the separation of the curves was readily apparent within the first 2 weeks.

The efficacy and tolerability of ruxolitinib appeared to be similar in younger children (ages 2-6) relative to older children.
 

Extension study in children near completion

Most of the patients who participated in TRUE AD-3 have been rolled over to the open-label extension trial, which is nearing completion. Those originally randomized to vehicle have been rerandomized to the lower or higher dose of ruxolitinib.

While this trial was focused on ruxolitinib as monotherapy, Thrasyvoulos Tzellos, MD, head of the department of dermatology, Nordland Hospital Trust, Bødo, Norway, questioned whether this is will be how it will be used in clinical practice. With the increasing array of therapies for AD, the “concept of combination therapy becomes more and more relevant,” he said after Dr. Eichenfield’s presentation.

Questioning whether an effective nonsteroidal anti-inflammatory agent like ruxolitinib should be considered a first-line treatment in mild disease or an adjunctive treatment for AD of any severity, he suggested that it might be best considered within a combination.

Dr. Eichenfield agreed. “Once we get the drug approved in a controlled trial, I think we then figure out how to use it in clinical practice.” Based on his own use of ruxolitinib in adults, he noted that he has not seen this drug replace other therapies so much as provide another option for control.

“We have an increasing armamentarium of drugs to use for involvement in different areas of the body in order to get more long-term control of disease,” he said. As an effective topical nonsteroidal drug, he believes its addition to clinical care in younger children, if approved, will be meaningful.

Dr. Eichenfield disclosed financial relationships with more multiple pharmaceutical companies, including Incyte, the manufacturer of ruxolitinib cream that provided funding for the True-AD trials. Dr. Tzellos reported financial relationships with AbbVie and UCB.

BERLIN – Based on a phase 3 trial, treatment with the topical Janus kinase (JAK) inhibitor ruxolitinib appears to be as safe and effective for the control of atopic dermatitis (AD) in children aged 2-11 years as previously shown in adolescents and adults for whom it already has an approved indication.

In this study – TRUE-AD3 – systemic exposure to ruxolitinib, which is selective for JAK1 and 2, was followed closely, and the low mean plasma concentrations “suggest systemic JAK inhibition is highly unlikely,” Lawrence F. Eichenfield, MD, professor of dermatology and pediatrics at the University of California, San Diego, said at the annual congress of the European Academy of Dermatology and Venereology.

Ted Bosworth/MDedge News

For example, at a plasma concentration no greater than 27 nM in both younger and older patients at 4 weeks and again at 8 weeks, the systemic exposure was about a tenth of that (281 nM) previously associated with myelosuppression, he reported.

Given the boxed warning for oral JAK inhibitors, which was based largely on a 2022 study in adults with rheumatoid arthritis that associated tofacitinib, a nonspecific JAK inhibitor, with an increased risk of thrombotic events in adults already at risk for these events, safety was a focus of this phase 3 trial. The boxed warning is also in the labeling for topical ruxolitinib, 1.5% (Opzelura), approved for treating to mild to moderate atopic dermatitis in patients 12 years of age and older.

Dr. Eichenfield said there were no significant safety signals in the younger pediatric population. “There were no treatment-emergent adverse events suggestive of systemic JAK inhibition,” he said. This not only included the absence of serious infections, cardiac events, thromboses, or malignancies, but there was no signal of hematologic abnormalities, such as change in hemoglobin or neutrophil count.
 

Application site reactions

Rather, in the study of children ages 2-11, the only adverse events associated with topical ruxolitinib not observed in the control arm, which received the vehicle alone, were application site reactions, such as pain, erythema, and irritation. None of these occurred in more than 3% of those randomized to ruxolitinib regardless of dose.

Overall, in the trial, which randomized 329 patients ages from 2 to under 12 years with mild to moderate AD to ruxolitinib 1.5% cream, ruxolitinib 0.75% cream, or vehicle in a 2:2:1 fashion, there were just two (0.8%) discontinuations in the ruxolitinib groups (one in each dosing arm). There were none in the vehicle arm.

The safety supports an expansion of the AD indication for topical ruxolitinib in young children, because the rates of response were very similar to that seen in adolescents and adults in the previously published TRUE AD-1 and TRUE AD-2 trials, he said.

For the primary endpoint of Investigator’s Global Assessment (IGA) score of 0 (clear) or 1 (almost clear) with at least a 2 grade improvement in IGA score from baseline, the response rates were 56.5%, 36.6%, and 10.8% for ruxolitinib 1.5%, ruxolitinib 0.75%, and vehicle respectively, at 8 weeks (P < .0001 for both doses relative to vehicle).

For the secondary efficacy endpoint of 75% or greater clearance on the Eczema Area and Severity Index, the rates were 67.2%, 51.5%, and 15.4%, for ruxolitinib 1.5%, ruxolitinib 0.75%, and vehicle respectively. Again, the advantage of both doses of ruxolitinib relative to vehicle was highly statistically significant (P < .0001).

Control of itch, evaluated with the Numerical Rating Scale was only evaluated in children 6-2 because of concern of the reliability of reporting in younger children. Control was defined as at least a 4-point improvement from baseline. It was achieved by 43.4%, 37.5%, and 29.7% by week 8 in the arms receiving the higher dose of ruxolitinib, the lower dose, and vehicle, respectively. The median time to achieving itch control was 11 days, 13 days, and 23 days, respectively. For all of these endpoints, the separation of the curves was readily apparent within the first 2 weeks.

The efficacy and tolerability of ruxolitinib appeared to be similar in younger children (ages 2-6) relative to older children.
 

Extension study in children near completion

Most of the patients who participated in TRUE AD-3 have been rolled over to the open-label extension trial, which is nearing completion. Those originally randomized to vehicle have been rerandomized to the lower or higher dose of ruxolitinib.

While this trial was focused on ruxolitinib as monotherapy, Thrasyvoulos Tzellos, MD, head of the department of dermatology, Nordland Hospital Trust, Bødo, Norway, questioned whether this is will be how it will be used in clinical practice. With the increasing array of therapies for AD, the “concept of combination therapy becomes more and more relevant,” he said after Dr. Eichenfield’s presentation.

Questioning whether an effective nonsteroidal anti-inflammatory agent like ruxolitinib should be considered a first-line treatment in mild disease or an adjunctive treatment for AD of any severity, he suggested that it might be best considered within a combination.

Dr. Eichenfield agreed. “Once we get the drug approved in a controlled trial, I think we then figure out how to use it in clinical practice.” Based on his own use of ruxolitinib in adults, he noted that he has not seen this drug replace other therapies so much as provide another option for control.

“We have an increasing armamentarium of drugs to use for involvement in different areas of the body in order to get more long-term control of disease,” he said. As an effective topical nonsteroidal drug, he believes its addition to clinical care in younger children, if approved, will be meaningful.

Dr. Eichenfield disclosed financial relationships with more multiple pharmaceutical companies, including Incyte, the manufacturer of ruxolitinib cream that provided funding for the True-AD trials. Dr. Tzellos reported financial relationships with AbbVie and UCB.

Amyotrophic lateral sclerosis (ALS) falls easily into the Food and Drug Administration definition of “rare disease.” With an estimated prevalence in the United States of fewer than 20,000 cases,¹ ALS sits comfortably below the cutoff of 200,000 cases that serves to define a disease as “rare.”

After a recent steep climb, there are something on the order of 50 therapies, across more than 10 drug classes, in clinical trials for the treatment of ALS.² This bounty represents exciting progress toward the development of targeted therapies for a characteristically fatal disease.

That headway is coupled with a sobering limitation, however: Relatively few ALS patients are being enrolled.
 

The knotty problem with therapeutic trials for ALS

“Trials are generally designed for patients with adequate functional reserve and predicted survival, to ensure that a signal of benefit can be seen,” said Nicholas John Maragakis, MD, director of the ALS Clinical Trials Unit at Johns Hopkins University, Baltimore. “Many of my patients are too severely affected at presentation.”

The generalist can make a difference in therapeutic success

The proliferation of clinical trials has made early diagnosis of ALS urgent. However, the experts interviewed for this article agreed: Accelerating the time to diagnosis is more dependent on the general neurologist or primary care physician than on the ALS specialist. ALS is a diagnosis of exclusion, but there is now very little delay in reaching a probable diagnosis at a dedicated center.

Yet neurodegenerative complaints in early-stage ALS are often nonspecific and mild; confidence in making a potential diagnosis of ALS is limited among primary care clinicians and general neurologists, who almost always see these patients first. Usually, the problem is not failure to include ALS in the differential diagnosis but hesitation in being candid when there is still doubt.

General neurologists, in particular, Dr. Maragakis said, “are often highly suspicious of a diagnosis of ALS very early on but are concerned about using this term until the clinical signs are more compelling.”

This is understandable. There is reluctance to deliver bad news when confidence in the diagnosis is limited. But the experts agreed: Delayed diagnosis is not in the patient’s interest now that there is at least the potential for entering a trial supported by a scientific rationale for benefit.

Where we stand: Pathophysiology, diagnosis, treatment

Pathophysiology. ALS is characterized by muscle denervation.⁴ In the great majority of cases, the disease represents a proteinopathy involving loss of the TDP-43 protein from nuclei. However, pathological heterogeneity means that other pathophysiological mechanisms – mediated by oxidative stress, mitochondrial dysfunction, and neurotoxicity related to excessive stimulation of postsynaptic glutamate receptors – can participate.^2,5,6

Comprehensive care at specialty centers

Whenever possible, ALS is a disease best managed at a center that offers comprehensive management, including multidisciplinary care. On this point, the four experts agreed.

“Tertiary-care centers for ALS serve a critical purpose,”

Dr. Maiser said. For a disease that affects nearly every aspect of life, the skills of a multidisciplinary support staff offer an “opportunity to stay in front of the disease” for as long as possible. Teamwork often leads to “outside-of-the-box thinking” for helping patients and families cope with the range of disabilities that undermine the patient’s quality of life.

Details of ALS management matter. At Mount Sinai and Hennepin Healthcare, and at Johns Hopkins, where demand recently led to the opening of a second ALS clinic, the ALS center is set up to address the full spectrum of needs. Staff members have multiple skills so that they can work together to make patients comfortable and prepare them for what is inevitably progression – even if the rate of that progression varies.

All these centers incorporate a rational, thorough discussion of end-of-life options in a palliative care approach that targets optimized quality of life. One goal is to prepare patients to consider and be prepared to make decisions when it is time for tracheostomy, percutaneous endoscopic gastrostomy, and other life support options that are not always well tolerated. The goal? Avoiding unnecessary anguish during end-stage disease when impaired respiratory function – the primary cause of ALS-related death – no longer sustains unassisted survival.

“I am concerned for the many ALS patients without access to this type of comprehensive care,” Dr. Macgowan said.

Like the other experts here, he emphasized that the demands of ALS care can be “overwhelming” outside a comprehensive care setting – for the patient, their family, and individual providers.
 

Looking ahead

There are many reasons to be optimistic about improving the survival and care of patients with ALS. Besides therapies in clinical trials, Dr. Scelsa explained, there is the potential role for monitoring neurofilament light changes, a biomarker of neurodegeneration, in patients who are at risk of ALS.

Dr. Maragakis offered an analogy to the gene therapy onasemnogene abeparvovec, which can prevent the associated neurodegeneration of spinal muscular atrophy if initiated before symptoms appear. He said that, in ALS, neurofilament light changes or other biomarkers might offer an opportunity to halt the progression of disease before it starts – if one or more therapies in development prove workable.

In the meantime, neurologists who do not specialize in ALS should be thinking about how they can participate in speedier diagnostic pathways.

“There are a number of therapies that look promising,” Dr. Maiser told Rare Neurological Disease Special Report. He singled out strategies to degrade TDP-43 or prevent it from forming. If these treatments are found effective, it’s expected that they would be of value in sporadic ALS, the most common form. Again, though, “the challenge is getting patients on this therapy at the earliest stages of disease.”

Dr. Maragakis discloses equity ownership/stock options with Braintrust Bio and Akava; he is a patent holder with Johns Hopkins [ALS] and has received grant/research/clinical trial support from Apellis Pharma, Biogen Idec, Cytokinetics, Helixmith, Calico, Sanofi, Department of Defense ALSRP, Maryland Stem Cell Research Fund, Massachusetts General Hospital, Medicinova, and NINDS. He serves as consultant or advisory board member for Amylyx; Cytokinetics, Roche, Healey Center, Nura Bio, Northeast ALS Consortium, Akava, Inflammx, and Secretome. Dr. Scelsa did not report any conflicts of interest. Dr. Macgowan and Dr. Maiser have no relevant conflicts of interest to disclose.
 

References

1. Mehta P et al. Prevalence of amyotrophic lateral sclerosis in the United States using established and novel methodologies, 2017. Amyotroph Lateral Scler Frontotemporal Degener. 2023;24(1-2):108-16. doi: 10.1080/21678421.2022.2059380.

2. Mead RJ et al. Amyotrophic lateral sclerosis: A neurodegenerative disorder poised for successful therapeutic translation. Nat Rev Drug Discov. 2023;22(3):185-212. doi: 10.1038/s41573-022-00612-2.

3. Longinetti E and Fang F. Epidemiology of amyotrophic lateral sclerosis: An update of recent literature. Curr Opin Neurol. 2019;32(5):771-6. doi: 10.1097/WCO.0000000000000730.

4. van den Bos MAJ et al. Pathophysiology and diagnosis of ALS: Insights from advances in neurophysiological techniques. Int J Mol Sci. 2019;20(11):2818. doi: 10.3390/ijms20112818.

5. Neumann M et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006;314(5796):130-3. doi: 10.1126/science.1134108.

6. Ling S-C et al. Converging mechanisms in ALS and FTD: Disrupted RNA and protein homeostasis. Neuron. 2013;79(3):416-38. doi: 10.1016/j.neuron.2013.07.033.

7. Ranganathan R et al. Multifaceted genes in amyotrophic lateral sclerosis-frontotemporal dementia. Front Neurosci. 2020;14:684. doi: 10.3389/fnins.2020.00684.

8. Ryan M et al. Lifetime risk and heritability of amyotrophic lateral sclerosis. JAMA Neurol. 2019;76(11):1367-74. doi: 10.1001/jamaneurol.2019.2044.

9. van Rheenen W et al. Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology. Nat Genet. 2021;53(12):1636-48. doi: 10.1038/s41588-021-00973-1.

10. Miller TM et al; VALOR and OLE Working Group. Trial of antisense oligonucleotide tofersen for SOD1 ALS. N Engl J Med. 2022;387(12):1099-110. doi: 10.1056/NEJMoa2204705.

Amyotrophic lateral sclerosis (ALS) falls easily into the Food and Drug Administration definition of “rare disease.” With an estimated prevalence in the United States of fewer than 20,000 cases,¹ ALS sits comfortably below the cutoff of 200,000 cases that serves to define a disease as “rare.”

After a recent steep climb, there are something on the order of 50 therapies, across more than 10 drug classes, in clinical trials for the treatment of ALS.² This bounty represents exciting progress toward the development of targeted therapies for a characteristically fatal disease.

That headway is coupled with a sobering limitation, however: Relatively few ALS patients are being enrolled.
 

The knotty problem with therapeutic trials for ALS

“Trials are generally designed for patients with adequate functional reserve and predicted survival, to ensure that a signal of benefit can be seen,” said Nicholas John Maragakis, MD, director of the ALS Clinical Trials Unit at Johns Hopkins University, Baltimore. “Many of my patients are too severely affected at presentation.”

The generalist can make a difference in therapeutic success

The proliferation of clinical trials has made early diagnosis of ALS urgent. However, the experts interviewed for this article agreed: Accelerating the time to diagnosis is more dependent on the general neurologist or primary care physician than on the ALS specialist. ALS is a diagnosis of exclusion, but there is now very little delay in reaching a probable diagnosis at a dedicated center.

Yet neurodegenerative complaints in early-stage ALS are often nonspecific and mild; confidence in making a potential diagnosis of ALS is limited among primary care clinicians and general neurologists, who almost always see these patients first. Usually, the problem is not failure to include ALS in the differential diagnosis but hesitation in being candid when there is still doubt.

General neurologists, in particular, Dr. Maragakis said, “are often highly suspicious of a diagnosis of ALS very early on but are concerned about using this term until the clinical signs are more compelling.”

This is understandable. There is reluctance to deliver bad news when confidence in the diagnosis is limited. But the experts agreed: Delayed diagnosis is not in the patient’s interest now that there is at least the potential for entering a trial supported by a scientific rationale for benefit.

Where we stand: Pathophysiology, diagnosis, treatment

Pathophysiology. ALS is characterized by muscle denervation.⁴ In the great majority of cases, the disease represents a proteinopathy involving loss of the TDP-43 protein from nuclei. However, pathological heterogeneity means that other pathophysiological mechanisms – mediated by oxidative stress, mitochondrial dysfunction, and neurotoxicity related to excessive stimulation of postsynaptic glutamate receptors – can participate.^2,5,6

Comprehensive care at specialty centers

Whenever possible, ALS is a disease best managed at a center that offers comprehensive management, including multidisciplinary care. On this point, the four experts agreed.

“Tertiary-care centers for ALS serve a critical purpose,”

Dr. Maiser said. For a disease that affects nearly every aspect of life, the skills of a multidisciplinary support staff offer an “opportunity to stay in front of the disease” for as long as possible. Teamwork often leads to “outside-of-the-box thinking” for helping patients and families cope with the range of disabilities that undermine the patient’s quality of life.

Details of ALS management matter. At Mount Sinai and Hennepin Healthcare, and at Johns Hopkins, where demand recently led to the opening of a second ALS clinic, the ALS center is set up to address the full spectrum of needs. Staff members have multiple skills so that they can work together to make patients comfortable and prepare them for what is inevitably progression – even if the rate of that progression varies.

All these centers incorporate a rational, thorough discussion of end-of-life options in a palliative care approach that targets optimized quality of life. One goal is to prepare patients to consider and be prepared to make decisions when it is time for tracheostomy, percutaneous endoscopic gastrostomy, and other life support options that are not always well tolerated. The goal? Avoiding unnecessary anguish during end-stage disease when impaired respiratory function – the primary cause of ALS-related death – no longer sustains unassisted survival.

“I am concerned for the many ALS patients without access to this type of comprehensive care,” Dr. Macgowan said.

Like the other experts here, he emphasized that the demands of ALS care can be “overwhelming” outside a comprehensive care setting – for the patient, their family, and individual providers.
 

Looking ahead

There are many reasons to be optimistic about improving the survival and care of patients with ALS. Besides therapies in clinical trials, Dr. Scelsa explained, there is the potential role for monitoring neurofilament light changes, a biomarker of neurodegeneration, in patients who are at risk of ALS.

Dr. Maragakis offered an analogy to the gene therapy onasemnogene abeparvovec, which can prevent the associated neurodegeneration of spinal muscular atrophy if initiated before symptoms appear. He said that, in ALS, neurofilament light changes or other biomarkers might offer an opportunity to halt the progression of disease before it starts – if one or more therapies in development prove workable.

In the meantime, neurologists who do not specialize in ALS should be thinking about how they can participate in speedier diagnostic pathways.

“There are a number of therapies that look promising,” Dr. Maiser told Rare Neurological Disease Special Report. He singled out strategies to degrade TDP-43 or prevent it from forming. If these treatments are found effective, it’s expected that they would be of value in sporadic ALS, the most common form. Again, though, “the challenge is getting patients on this therapy at the earliest stages of disease.”

Dr. Maragakis discloses equity ownership/stock options with Braintrust Bio and Akava; he is a patent holder with Johns Hopkins [ALS] and has received grant/research/clinical trial support from Apellis Pharma, Biogen Idec, Cytokinetics, Helixmith, Calico, Sanofi, Department of Defense ALSRP, Maryland Stem Cell Research Fund, Massachusetts General Hospital, Medicinova, and NINDS. He serves as consultant or advisory board member for Amylyx; Cytokinetics, Roche, Healey Center, Nura Bio, Northeast ALS Consortium, Akava, Inflammx, and Secretome. Dr. Scelsa did not report any conflicts of interest. Dr. Macgowan and Dr. Maiser have no relevant conflicts of interest to disclose.
 

References

1. Mehta P et al. Prevalence of amyotrophic lateral sclerosis in the United States using established and novel methodologies, 2017. Amyotroph Lateral Scler Frontotemporal Degener. 2023;24(1-2):108-16. doi: 10.1080/21678421.2022.2059380.

2. Mead RJ et al. Amyotrophic lateral sclerosis: A neurodegenerative disorder poised for successful therapeutic translation. Nat Rev Drug Discov. 2023;22(3):185-212. doi: 10.1038/s41573-022-00612-2.

3. Longinetti E and Fang F. Epidemiology of amyotrophic lateral sclerosis: An update of recent literature. Curr Opin Neurol. 2019;32(5):771-6. doi: 10.1097/WCO.0000000000000730.

4. van den Bos MAJ et al. Pathophysiology and diagnosis of ALS: Insights from advances in neurophysiological techniques. Int J Mol Sci. 2019;20(11):2818. doi: 10.3390/ijms20112818.

5. Neumann M et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006;314(5796):130-3. doi: 10.1126/science.1134108.

6. Ling S-C et al. Converging mechanisms in ALS and FTD: Disrupted RNA and protein homeostasis. Neuron. 2013;79(3):416-38. doi: 10.1016/j.neuron.2013.07.033.

7. Ranganathan R et al. Multifaceted genes in amyotrophic lateral sclerosis-frontotemporal dementia. Front Neurosci. 2020;14:684. doi: 10.3389/fnins.2020.00684.

8. Ryan M et al. Lifetime risk and heritability of amyotrophic lateral sclerosis. JAMA Neurol. 2019;76(11):1367-74. doi: 10.1001/jamaneurol.2019.2044.

9. van Rheenen W et al. Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology. Nat Genet. 2021;53(12):1636-48. doi: 10.1038/s41588-021-00973-1.

10. Miller TM et al; VALOR and OLE Working Group. Trial of antisense oligonucleotide tofersen for SOD1 ALS. N Engl J Med. 2022;387(12):1099-110. doi: 10.1056/NEJMoa2204705.

Amyotrophic lateral sclerosis (ALS) falls easily into the Food and Drug Administration definition of “rare disease.” With an estimated prevalence in the United States of fewer than 20,000 cases,¹ ALS sits comfortably below the cutoff of 200,000 cases that serves to define a disease as “rare.”

After a recent steep climb, there are something on the order of 50 therapies, across more than 10 drug classes, in clinical trials for the treatment of ALS.² This bounty represents exciting progress toward the development of targeted therapies for a characteristically fatal disease.

That headway is coupled with a sobering limitation, however: Relatively few ALS patients are being enrolled.
 

The knotty problem with therapeutic trials for ALS

“Trials are generally designed for patients with adequate functional reserve and predicted survival, to ensure that a signal of benefit can be seen,” said Nicholas John Maragakis, MD, director of the ALS Clinical Trials Unit at Johns Hopkins University, Baltimore. “Many of my patients are too severely affected at presentation.”

The generalist can make a difference in therapeutic success

The proliferation of clinical trials has made early diagnosis of ALS urgent. However, the experts interviewed for this article agreed: Accelerating the time to diagnosis is more dependent on the general neurologist or primary care physician than on the ALS specialist. ALS is a diagnosis of exclusion, but there is now very little delay in reaching a probable diagnosis at a dedicated center.

Yet neurodegenerative complaints in early-stage ALS are often nonspecific and mild; confidence in making a potential diagnosis of ALS is limited among primary care clinicians and general neurologists, who almost always see these patients first. Usually, the problem is not failure to include ALS in the differential diagnosis but hesitation in being candid when there is still doubt.

General neurologists, in particular, Dr. Maragakis said, “are often highly suspicious of a diagnosis of ALS very early on but are concerned about using this term until the clinical signs are more compelling.”

This is understandable. There is reluctance to deliver bad news when confidence in the diagnosis is limited. But the experts agreed: Delayed diagnosis is not in the patient’s interest now that there is at least the potential for entering a trial supported by a scientific rationale for benefit.

Where we stand: Pathophysiology, diagnosis, treatment

Pathophysiology. ALS is characterized by muscle denervation.⁴ In the great majority of cases, the disease represents a proteinopathy involving loss of the TDP-43 protein from nuclei. However, pathological heterogeneity means that other pathophysiological mechanisms – mediated by oxidative stress, mitochondrial dysfunction, and neurotoxicity related to excessive stimulation of postsynaptic glutamate receptors – can participate.^2,5,6

Comprehensive care at specialty centers

Whenever possible, ALS is a disease best managed at a center that offers comprehensive management, including multidisciplinary care. On this point, the four experts agreed.

“Tertiary-care centers for ALS serve a critical purpose,”

Dr. Maiser said. For a disease that affects nearly every aspect of life, the skills of a multidisciplinary support staff offer an “opportunity to stay in front of the disease” for as long as possible. Teamwork often leads to “outside-of-the-box thinking” for helping patients and families cope with the range of disabilities that undermine the patient’s quality of life.

Details of ALS management matter. At Mount Sinai and Hennepin Healthcare, and at Johns Hopkins, where demand recently led to the opening of a second ALS clinic, the ALS center is set up to address the full spectrum of needs. Staff members have multiple skills so that they can work together to make patients comfortable and prepare them for what is inevitably progression – even if the rate of that progression varies.

All these centers incorporate a rational, thorough discussion of end-of-life options in a palliative care approach that targets optimized quality of life. One goal is to prepare patients to consider and be prepared to make decisions when it is time for tracheostomy, percutaneous endoscopic gastrostomy, and other life support options that are not always well tolerated. The goal? Avoiding unnecessary anguish during end-stage disease when impaired respiratory function – the primary cause of ALS-related death – no longer sustains unassisted survival.

“I am concerned for the many ALS patients without access to this type of comprehensive care,” Dr. Macgowan said.

Like the other experts here, he emphasized that the demands of ALS care can be “overwhelming” outside a comprehensive care setting – for the patient, their family, and individual providers.
 

Looking ahead

There are many reasons to be optimistic about improving the survival and care of patients with ALS. Besides therapies in clinical trials, Dr. Scelsa explained, there is the potential role for monitoring neurofilament light changes, a biomarker of neurodegeneration, in patients who are at risk of ALS.

Dr. Maragakis offered an analogy to the gene therapy onasemnogene abeparvovec, which can prevent the associated neurodegeneration of spinal muscular atrophy if initiated before symptoms appear. He said that, in ALS, neurofilament light changes or other biomarkers might offer an opportunity to halt the progression of disease before it starts – if one or more therapies in development prove workable.

In the meantime, neurologists who do not specialize in ALS should be thinking about how they can participate in speedier diagnostic pathways.

“There are a number of therapies that look promising,” Dr. Maiser told Rare Neurological Disease Special Report. He singled out strategies to degrade TDP-43 or prevent it from forming. If these treatments are found effective, it’s expected that they would be of value in sporadic ALS, the most common form. Again, though, “the challenge is getting patients on this therapy at the earliest stages of disease.”

Dr. Maragakis discloses equity ownership/stock options with Braintrust Bio and Akava; he is a patent holder with Johns Hopkins [ALS] and has received grant/research/clinical trial support from Apellis Pharma, Biogen Idec, Cytokinetics, Helixmith, Calico, Sanofi, Department of Defense ALSRP, Maryland Stem Cell Research Fund, Massachusetts General Hospital, Medicinova, and NINDS. He serves as consultant or advisory board member for Amylyx; Cytokinetics, Roche, Healey Center, Nura Bio, Northeast ALS Consortium, Akava, Inflammx, and Secretome. Dr. Scelsa did not report any conflicts of interest. Dr. Macgowan and Dr. Maiser have no relevant conflicts of interest to disclose.
 

References

1. Mehta P et al. Prevalence of amyotrophic lateral sclerosis in the United States using established and novel methodologies, 2017. Amyotroph Lateral Scler Frontotemporal Degener. 2023;24(1-2):108-16. doi: 10.1080/21678421.2022.2059380.

2. Mead RJ et al. Amyotrophic lateral sclerosis: A neurodegenerative disorder poised for successful therapeutic translation. Nat Rev Drug Discov. 2023;22(3):185-212. doi: 10.1038/s41573-022-00612-2.

3. Longinetti E and Fang F. Epidemiology of amyotrophic lateral sclerosis: An update of recent literature. Curr Opin Neurol. 2019;32(5):771-6. doi: 10.1097/WCO.0000000000000730.

4. van den Bos MAJ et al. Pathophysiology and diagnosis of ALS: Insights from advances in neurophysiological techniques. Int J Mol Sci. 2019;20(11):2818. doi: 10.3390/ijms20112818.

5. Neumann M et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006;314(5796):130-3. doi: 10.1126/science.1134108.

6. Ling S-C et al. Converging mechanisms in ALS and FTD: Disrupted RNA and protein homeostasis. Neuron. 2013;79(3):416-38. doi: 10.1016/j.neuron.2013.07.033.

7. Ranganathan R et al. Multifaceted genes in amyotrophic lateral sclerosis-frontotemporal dementia. Front Neurosci. 2020;14:684. doi: 10.3389/fnins.2020.00684.

8. Ryan M et al. Lifetime risk and heritability of amyotrophic lateral sclerosis. JAMA Neurol. 2019;76(11):1367-74. doi: 10.1001/jamaneurol.2019.2044.

9. van Rheenen W et al. Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology. Nat Genet. 2021;53(12):1636-48. doi: 10.1038/s41588-021-00973-1.

10. Miller TM et al; VALOR and OLE Working Group. Trial of antisense oligonucleotide tofersen for SOD1 ALS. N Engl J Med. 2022;387(12):1099-110. doi: 10.1056/NEJMoa2204705.

The first randomized trial to evaluate postprocedural anticoagulation (PPA) in patients undergoing a primary percutaneous coronary intervention (PCI) for an ST-segment elevation myocardial infarction (STEMI) did not associate significant benefit – or significant harm – with any of the three tested regimens relative to placebo.

There has been a signal from nonrandomized studies that PPA reduces the risk for ischemic events, but no controlled prospective trials have evaluated the risk-benefit relationship in STEMI patients, said Yan Yan, MD, a researcher in Beijing Anzhen Hospital.

The results of the randomized trial, called RIGHT, were presented at the annual congress of the European Society of Cardiology by Dr. Yan, on behalf of a team of coinvestigators led by Nie Shaoping, MD, PhD, a cardiologist affiliated with Capital Medical University, Beijing.

The bottom line is that “routine PPA with low-dose anticoagulation after primary PCI in STEMI patients is safe, but it does not improve ischemic outcome at 30 days,” Dr. Yan concluded.
 

Objective study

In her presentation, Dr. Yan explained that an objective study has been needed to validate the common use of empirically administered PPA. According to Dr. Yan, PPA is being offered to up to 40% of STEMI patients in Europe, with even higher rates in China.

In the investigator-initiated RIGHT trial, 2,856 STEMI patients undergoing PCI were randomized to PPA or placebo in a 1:1 ratio. In the PPA arm, patients received one of three low-dose anticoagulation regimens over 48 hours or until discharge if this was longer: 0.2 mg/kg per hour of bivalirudin administered intravenously; 40 mg of enoxaparin administered subcutaneously; or 10 U/kg per hour of unfractionated heparin (UFH) to maintain an activated coagulation time between 150 and 200 seconds.

Each of the 53 participating Chinese centers selected one of the anticoagulation regimens. Matching placebos were employed in the double-blind design. All received bivalirudin anticoagulation during PCI. Exclusion criteria included unstable disease, such as cardiogenic shock, prior coronary artery bypass grafting, or an indication for anticoagulation other than PPA.

For the composite primary endpoint of all-cause death, nonfatal MI, nonfatal stroke, stent thrombosis, or urgent revascularization at 30 days, there was no difference between PPA and placebo. The event rate in both arms was 2.5%.

There were also no significant differences between PPA and placebo for any of the secondary ischemic endpoints, which included the individual components of the primary endpoint and cardiovascular death.

For the primary safety endpoint of Bleeding Academic Research Consortium (BARC) grade 3-5 bleeding, the slight increase in events among those in the placebo group did not approach statistical significance (P = .551). On other definitions of bleeding, which were secondary endpoints, PPA and placebo also did not differ significantly.

Compared for safety, the three anticoagulation regimens performed similarly with no significant interaction for the primary endpoint (P = .679).

For efficacy, the differences did range sufficiently to produce a significant interaction (P = .01) with enoxaparin appearing to be more effective, UFH less effective, and bivalirudin falling in between. This led Dr. Yan to speculate that the three anticoagulants “may not be equivalent,” although she said larger trials are needed to explore potential differences.
 

Design flawed?

The ESC-invited discussant, Pascal Vranckx, MD, PhD, medical director, cardiac critical care services, Hartcentrum Hasselt, Belgium, liked the question being asked in the study, but concluded that the design was flawed.

“There are a variety of anticoagulants employed in a variety of doses [for PPA] but we have very limited data. The research question is totally appropriate,” he said. However, he asked, “What went wrong? Was it the drugs, the trial, or both?”

The problem, he thinks, is the dose. Much of the design of RIGHT was based on the 2015 MATRIX trial, which did show a benefit from a single dose of bivalirudin following PCI relative to two other comparators. In that study, STEMI patients randomized to bivalirudin received a bolus of 0.75 mg/kg followed by an infusion of 1.75 mg/kg per hour for at least 4 hours. The comparators were UFH or a control arm of low-molecular-weight heparin with optional glycoprotein IIb/IIIa inhibitors.

At 30 days, bivalirudin was associated with a 40% reduction (hazard ratio, 0.60; P = .001) relative to control for the composite primary endpoint of death or bleeding. Dr. Vranckx pointed out that MATRIX was a trial of a single-dose prolongation of PPA, whereas RIGHT was “a prolongation of a prolongation,” but he believes MATRIX data support higher doses of anticoagulation, particularly of bivalirudin.

“Perhaps low dose bivalirudin is not the way to go,” he speculated.

He further advised the authors to reevaluate the expected benefit from PPA following STEMI. In MATRIX, the risk for events was highly concentrated in the immediate period after PCI, suggesting that the opportunity to reduce risk is much lower as anticoagulation is prolonged. He suggested that the low number of events in RIGHT are consistent with the diminishing risk for events over time.

Nevertheless, Dr. Vranckx praised the authors for addressing a research question that is “timely and highly relevant.” He called the data “important” by drawing attention to a potential target for risk reduction, and encouraged additional trials to determine what PPA strategy, if any, can further reduce early ischemic events after PCI.

Dr. Yan and colleagues report financial relationships with Abbott, Boston Scientific, East China Pharmaceuticals, Saniju Medical and Pharmaceuticals, and Jiangsu Hengrui Pharmaceuticals, which provided funding for this study. Dr. Vranckx reports no potential conflicts of interest.

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

The first randomized trial to evaluate postprocedural anticoagulation (PPA) in patients undergoing a primary percutaneous coronary intervention (PCI) for an ST-segment elevation myocardial infarction (STEMI) did not associate significant benefit – or significant harm – with any of the three tested regimens relative to placebo.

There has been a signal from nonrandomized studies that PPA reduces the risk for ischemic events, but no controlled prospective trials have evaluated the risk-benefit relationship in STEMI patients, said Yan Yan, MD, a researcher in Beijing Anzhen Hospital.

The results of the randomized trial, called RIGHT, were presented at the annual congress of the European Society of Cardiology by Dr. Yan, on behalf of a team of coinvestigators led by Nie Shaoping, MD, PhD, a cardiologist affiliated with Capital Medical University, Beijing.

The bottom line is that “routine PPA with low-dose anticoagulation after primary PCI in STEMI patients is safe, but it does not improve ischemic outcome at 30 days,” Dr. Yan concluded.
 

Objective study

In her presentation, Dr. Yan explained that an objective study has been needed to validate the common use of empirically administered PPA. According to Dr. Yan, PPA is being offered to up to 40% of STEMI patients in Europe, with even higher rates in China.

In the investigator-initiated RIGHT trial, 2,856 STEMI patients undergoing PCI were randomized to PPA or placebo in a 1:1 ratio. In the PPA arm, patients received one of three low-dose anticoagulation regimens over 48 hours or until discharge if this was longer: 0.2 mg/kg per hour of bivalirudin administered intravenously; 40 mg of enoxaparin administered subcutaneously; or 10 U/kg per hour of unfractionated heparin (UFH) to maintain an activated coagulation time between 150 and 200 seconds.

Each of the 53 participating Chinese centers selected one of the anticoagulation regimens. Matching placebos were employed in the double-blind design. All received bivalirudin anticoagulation during PCI. Exclusion criteria included unstable disease, such as cardiogenic shock, prior coronary artery bypass grafting, or an indication for anticoagulation other than PPA.

For the composite primary endpoint of all-cause death, nonfatal MI, nonfatal stroke, stent thrombosis, or urgent revascularization at 30 days, there was no difference between PPA and placebo. The event rate in both arms was 2.5%.

There were also no significant differences between PPA and placebo for any of the secondary ischemic endpoints, which included the individual components of the primary endpoint and cardiovascular death.

For the primary safety endpoint of Bleeding Academic Research Consortium (BARC) grade 3-5 bleeding, the slight increase in events among those in the placebo group did not approach statistical significance (P = .551). On other definitions of bleeding, which were secondary endpoints, PPA and placebo also did not differ significantly.

Compared for safety, the three anticoagulation regimens performed similarly with no significant interaction for the primary endpoint (P = .679).

For efficacy, the differences did range sufficiently to produce a significant interaction (P = .01) with enoxaparin appearing to be more effective, UFH less effective, and bivalirudin falling in between. This led Dr. Yan to speculate that the three anticoagulants “may not be equivalent,” although she said larger trials are needed to explore potential differences.
 

Design flawed?

The ESC-invited discussant, Pascal Vranckx, MD, PhD, medical director, cardiac critical care services, Hartcentrum Hasselt, Belgium, liked the question being asked in the study, but concluded that the design was flawed.

“There are a variety of anticoagulants employed in a variety of doses [for PPA] but we have very limited data. The research question is totally appropriate,” he said. However, he asked, “What went wrong? Was it the drugs, the trial, or both?”

The problem, he thinks, is the dose. Much of the design of RIGHT was based on the 2015 MATRIX trial, which did show a benefit from a single dose of bivalirudin following PCI relative to two other comparators. In that study, STEMI patients randomized to bivalirudin received a bolus of 0.75 mg/kg followed by an infusion of 1.75 mg/kg per hour for at least 4 hours. The comparators were UFH or a control arm of low-molecular-weight heparin with optional glycoprotein IIb/IIIa inhibitors.

At 30 days, bivalirudin was associated with a 40% reduction (hazard ratio, 0.60; P = .001) relative to control for the composite primary endpoint of death or bleeding. Dr. Vranckx pointed out that MATRIX was a trial of a single-dose prolongation of PPA, whereas RIGHT was “a prolongation of a prolongation,” but he believes MATRIX data support higher doses of anticoagulation, particularly of bivalirudin.

“Perhaps low dose bivalirudin is not the way to go,” he speculated.

He further advised the authors to reevaluate the expected benefit from PPA following STEMI. In MATRIX, the risk for events was highly concentrated in the immediate period after PCI, suggesting that the opportunity to reduce risk is much lower as anticoagulation is prolonged. He suggested that the low number of events in RIGHT are consistent with the diminishing risk for events over time.

Nevertheless, Dr. Vranckx praised the authors for addressing a research question that is “timely and highly relevant.” He called the data “important” by drawing attention to a potential target for risk reduction, and encouraged additional trials to determine what PPA strategy, if any, can further reduce early ischemic events after PCI.

Dr. Yan and colleagues report financial relationships with Abbott, Boston Scientific, East China Pharmaceuticals, Saniju Medical and Pharmaceuticals, and Jiangsu Hengrui Pharmaceuticals, which provided funding for this study. Dr. Vranckx reports no potential conflicts of interest.

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

The first randomized trial to evaluate postprocedural anticoagulation (PPA) in patients undergoing a primary percutaneous coronary intervention (PCI) for an ST-segment elevation myocardial infarction (STEMI) did not associate significant benefit – or significant harm – with any of the three tested regimens relative to placebo.

There has been a signal from nonrandomized studies that PPA reduces the risk for ischemic events, but no controlled prospective trials have evaluated the risk-benefit relationship in STEMI patients, said Yan Yan, MD, a researcher in Beijing Anzhen Hospital.

The results of the randomized trial, called RIGHT, were presented at the annual congress of the European Society of Cardiology by Dr. Yan, on behalf of a team of coinvestigators led by Nie Shaoping, MD, PhD, a cardiologist affiliated with Capital Medical University, Beijing.

The bottom line is that “routine PPA with low-dose anticoagulation after primary PCI in STEMI patients is safe, but it does not improve ischemic outcome at 30 days,” Dr. Yan concluded.
 

Objective study

In her presentation, Dr. Yan explained that an objective study has been needed to validate the common use of empirically administered PPA. According to Dr. Yan, PPA is being offered to up to 40% of STEMI patients in Europe, with even higher rates in China.

In the investigator-initiated RIGHT trial, 2,856 STEMI patients undergoing PCI were randomized to PPA or placebo in a 1:1 ratio. In the PPA arm, patients received one of three low-dose anticoagulation regimens over 48 hours or until discharge if this was longer: 0.2 mg/kg per hour of bivalirudin administered intravenously; 40 mg of enoxaparin administered subcutaneously; or 10 U/kg per hour of unfractionated heparin (UFH) to maintain an activated coagulation time between 150 and 200 seconds.

Each of the 53 participating Chinese centers selected one of the anticoagulation regimens. Matching placebos were employed in the double-blind design. All received bivalirudin anticoagulation during PCI. Exclusion criteria included unstable disease, such as cardiogenic shock, prior coronary artery bypass grafting, or an indication for anticoagulation other than PPA.

For the composite primary endpoint of all-cause death, nonfatal MI, nonfatal stroke, stent thrombosis, or urgent revascularization at 30 days, there was no difference between PPA and placebo. The event rate in both arms was 2.5%.

There were also no significant differences between PPA and placebo for any of the secondary ischemic endpoints, which included the individual components of the primary endpoint and cardiovascular death.

For the primary safety endpoint of Bleeding Academic Research Consortium (BARC) grade 3-5 bleeding, the slight increase in events among those in the placebo group did not approach statistical significance (P = .551). On other definitions of bleeding, which were secondary endpoints, PPA and placebo also did not differ significantly.

Compared for safety, the three anticoagulation regimens performed similarly with no significant interaction for the primary endpoint (P = .679).

For efficacy, the differences did range sufficiently to produce a significant interaction (P = .01) with enoxaparin appearing to be more effective, UFH less effective, and bivalirudin falling in between. This led Dr. Yan to speculate that the three anticoagulants “may not be equivalent,” although she said larger trials are needed to explore potential differences.
 

Design flawed?

The ESC-invited discussant, Pascal Vranckx, MD, PhD, medical director, cardiac critical care services, Hartcentrum Hasselt, Belgium, liked the question being asked in the study, but concluded that the design was flawed.

“There are a variety of anticoagulants employed in a variety of doses [for PPA] but we have very limited data. The research question is totally appropriate,” he said. However, he asked, “What went wrong? Was it the drugs, the trial, or both?”

The problem, he thinks, is the dose. Much of the design of RIGHT was based on the 2015 MATRIX trial, which did show a benefit from a single dose of bivalirudin following PCI relative to two other comparators. In that study, STEMI patients randomized to bivalirudin received a bolus of 0.75 mg/kg followed by an infusion of 1.75 mg/kg per hour for at least 4 hours. The comparators were UFH or a control arm of low-molecular-weight heparin with optional glycoprotein IIb/IIIa inhibitors.

At 30 days, bivalirudin was associated with a 40% reduction (hazard ratio, 0.60; P = .001) relative to control for the composite primary endpoint of death or bleeding. Dr. Vranckx pointed out that MATRIX was a trial of a single-dose prolongation of PPA, whereas RIGHT was “a prolongation of a prolongation,” but he believes MATRIX data support higher doses of anticoagulation, particularly of bivalirudin.

“Perhaps low dose bivalirudin is not the way to go,” he speculated.

He further advised the authors to reevaluate the expected benefit from PPA following STEMI. In MATRIX, the risk for events was highly concentrated in the immediate period after PCI, suggesting that the opportunity to reduce risk is much lower as anticoagulation is prolonged. He suggested that the low number of events in RIGHT are consistent with the diminishing risk for events over time.

Nevertheless, Dr. Vranckx praised the authors for addressing a research question that is “timely and highly relevant.” He called the data “important” by drawing attention to a potential target for risk reduction, and encouraged additional trials to determine what PPA strategy, if any, can further reduce early ischemic events after PCI.

Dr. Yan and colleagues report financial relationships with Abbott, Boston Scientific, East China Pharmaceuticals, Saniju Medical and Pharmaceuticals, and Jiangsu Hengrui Pharmaceuticals, which provided funding for this study. Dr. Vranckx reports no potential conflicts of interest.

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

The European Society of Cardiology has released new guidelines for cardiomyopathies, their first major comprehensive international guidelines to address diagnosis and treatment of the broad causes of heart muscle dysfunction.

The document was released in conjunction with the annual congress of the European Society of Cardiology and is also available online in the European Heart Journal.

“We have considered cardiomyopathies across the life course from pediatric to adult,” explained Elena Arbelo, MD, PhD, coordinator of the cardiac genetic diseases and sudden arrhythmic death unit, Hospital Clinic de Barcelona. Dr. Arbelo is first author and one of two chairpersons of the ESC task force that brought the guidelines forward.

Not an update, the ESC guidelines are the first to “include all cardiomyopathy subtypes, and the first time that specific recommendations are made for cardiomyopathies other than hypertrophic cardiomyopathy” (HCM), Dr. Arbelo said.
 

Guidelines organize cardiomyopathy phenotypes

Cardiomyopathy can present at any age. It can have multiple complex etiologies, including genetic predisposition, heart muscle injury caused by disease, or a mix of participating factors. The ESC task force employed several strategies in taking a comprehensive approach to the condition, said Juan Kaski, MD, PhD, professor of pediatric inherited cardiovascular medicine at the University College of London.

“From my point of view, the key innovations include a diagnostic workup that starts with a detailed phenotypic description, including the new phenotype of nondilated left ventricular cardiomyopathy, that then triggers a multiparametric, systematic evaluation,” said Dr. Kaski, cochair of the task force.

As explained in the introduction to the guideline and reiterated by both Dr. Arbelo and Dr. Kaski, the guidelines have been organized around the patient pathway, meaning that focus should be placed on recognizing the presenting phenotype as a critical first step in discerning the underlying etiology and its treatments.

“Central to this approach is not only the individual patient but also the family as a whole,” Dr. Arbelo said. “Clinical findings in relatives are essential for understanding what happens to the patient and vice versa.”
 

Genetic testing in children described

The new guidelines include specific recommendations about genetic testing of children. They also emphasize the value of cardiovascular magnetic resonance (CMR) imaging in the “diagnosis, screening, monitoring, and prognostication” for patients of all ages, according to Dr. Kaski.

“CMR is recommended at the initial evaluation for every patient with cardiomyopathy,” Dr. Arbelo said. It should be “considered” during follow-up and for many other applications, including the evaluation of “genotype-positive but phenotype-negative relatives.”

Etiologic prediction models have been incorporated into the guidelines, including genotyping for dilated cardiomyopathies and nondilated left ventricular cardiomyopathy, said both Dr. Arbelo and Dr. Kaski, interviewed separately. They both indicated that the task force did their best to make the guidelines user friendly.

Each of the recommendations in the guidelines is provided with an evidence-based classification. In order, these are class I (recommended), class IIa (should be considered), class IIb (may be considered), and class III (not recommended).
 

Many symptoms are cardiomyopathy related

Dr. Kaski and Dr. Arbelo both emphasized that the guidelines draw attention to the relationship of cardiomyopathy to common cardiovascular conditions, such as heart failure, arrhythmia, and chest pain. Dr. Kaski pointed out that these are the types of problems commonly encountered by general cardiologists and well as primary care physicians.

In 2014, the ESC published guidelines specific to HCM. The new broader guidelines do not overlook this subtype. According to Dr. Kaski, there have been several innovations in HCM since the previous guidelines, such as when to consider cardiac myosin inhibitors for symptomatic left ventricular outflow tract obstruction.

The ESC guidelines place an emphasis on a “coordinated, systematic, and individualized” care pathway based on a multidisciplinary approach, according to Dr. Arbelo. Although the composition of the interdisciplinary team depends on the individual case, the guidelines recognize a key role for general cardiologists in managing the majority of patients. Suggestions of when to refer challenging cases to expert centers are outlined.
 

32 key messages derived from guidelines

The guidelines include almost 90 pages of recommendations. The task force isolated 32 key messages from 13 sections ranging from descriptions of how the patient pathway is defined to what types of physical activity should be considered for different forms of cardiomyopathy. There is also a section devoted to important gaps in evidence and areas in which there is the most need for further studies.

The guidelines end with a comprehensive list of “what to do” and “what not to do” in the diagnosis and care of cardiomyopathy. These include most of the class I recommendations and summarize some important class III cautions.

“Most of the recommendations in the guideline are new,” the authors wrote in the introduction. Although they acknowledged that they did not attempt to provide detailed recommendations for every cardiomyopathy phenotype, they endeavored to cover general evaluation and management issues supported by relevant evidence.

Dr. Arbelo and Dr. Kaski disclosed no relevant financial relationships.

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

The European Society of Cardiology has released new guidelines for cardiomyopathies, their first major comprehensive international guidelines to address diagnosis and treatment of the broad causes of heart muscle dysfunction.

The document was released in conjunction with the annual congress of the European Society of Cardiology and is also available online in the European Heart Journal.

“We have considered cardiomyopathies across the life course from pediatric to adult,” explained Elena Arbelo, MD, PhD, coordinator of the cardiac genetic diseases and sudden arrhythmic death unit, Hospital Clinic de Barcelona. Dr. Arbelo is first author and one of two chairpersons of the ESC task force that brought the guidelines forward.

Not an update, the ESC guidelines are the first to “include all cardiomyopathy subtypes, and the first time that specific recommendations are made for cardiomyopathies other than hypertrophic cardiomyopathy” (HCM), Dr. Arbelo said.
 

Guidelines organize cardiomyopathy phenotypes

Cardiomyopathy can present at any age. It can have multiple complex etiologies, including genetic predisposition, heart muscle injury caused by disease, or a mix of participating factors. The ESC task force employed several strategies in taking a comprehensive approach to the condition, said Juan Kaski, MD, PhD, professor of pediatric inherited cardiovascular medicine at the University College of London.

“From my point of view, the key innovations include a diagnostic workup that starts with a detailed phenotypic description, including the new phenotype of nondilated left ventricular cardiomyopathy, that then triggers a multiparametric, systematic evaluation,” said Dr. Kaski, cochair of the task force.

As explained in the introduction to the guideline and reiterated by both Dr. Arbelo and Dr. Kaski, the guidelines have been organized around the patient pathway, meaning that focus should be placed on recognizing the presenting phenotype as a critical first step in discerning the underlying etiology and its treatments.

“Central to this approach is not only the individual patient but also the family as a whole,” Dr. Arbelo said. “Clinical findings in relatives are essential for understanding what happens to the patient and vice versa.”
 

Genetic testing in children described

The new guidelines include specific recommendations about genetic testing of children. They also emphasize the value of cardiovascular magnetic resonance (CMR) imaging in the “diagnosis, screening, monitoring, and prognostication” for patients of all ages, according to Dr. Kaski.

“CMR is recommended at the initial evaluation for every patient with cardiomyopathy,” Dr. Arbelo said. It should be “considered” during follow-up and for many other applications, including the evaluation of “genotype-positive but phenotype-negative relatives.”

Etiologic prediction models have been incorporated into the guidelines, including genotyping for dilated cardiomyopathies and nondilated left ventricular cardiomyopathy, said both Dr. Arbelo and Dr. Kaski, interviewed separately. They both indicated that the task force did their best to make the guidelines user friendly.

Each of the recommendations in the guidelines is provided with an evidence-based classification. In order, these are class I (recommended), class IIa (should be considered), class IIb (may be considered), and class III (not recommended).
 

Many symptoms are cardiomyopathy related

Dr. Kaski and Dr. Arbelo both emphasized that the guidelines draw attention to the relationship of cardiomyopathy to common cardiovascular conditions, such as heart failure, arrhythmia, and chest pain. Dr. Kaski pointed out that these are the types of problems commonly encountered by general cardiologists and well as primary care physicians.

In 2014, the ESC published guidelines specific to HCM. The new broader guidelines do not overlook this subtype. According to Dr. Kaski, there have been several innovations in HCM since the previous guidelines, such as when to consider cardiac myosin inhibitors for symptomatic left ventricular outflow tract obstruction.

The ESC guidelines place an emphasis on a “coordinated, systematic, and individualized” care pathway based on a multidisciplinary approach, according to Dr. Arbelo. Although the composition of the interdisciplinary team depends on the individual case, the guidelines recognize a key role for general cardiologists in managing the majority of patients. Suggestions of when to refer challenging cases to expert centers are outlined.
 

32 key messages derived from guidelines

The guidelines include almost 90 pages of recommendations. The task force isolated 32 key messages from 13 sections ranging from descriptions of how the patient pathway is defined to what types of physical activity should be considered for different forms of cardiomyopathy. There is also a section devoted to important gaps in evidence and areas in which there is the most need for further studies.

The guidelines end with a comprehensive list of “what to do” and “what not to do” in the diagnosis and care of cardiomyopathy. These include most of the class I recommendations and summarize some important class III cautions.

“Most of the recommendations in the guideline are new,” the authors wrote in the introduction. Although they acknowledged that they did not attempt to provide detailed recommendations for every cardiomyopathy phenotype, they endeavored to cover general evaluation and management issues supported by relevant evidence.

Dr. Arbelo and Dr. Kaski disclosed no relevant financial relationships.

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

The European Society of Cardiology has released new guidelines for cardiomyopathies, their first major comprehensive international guidelines to address diagnosis and treatment of the broad causes of heart muscle dysfunction.

The document was released in conjunction with the annual congress of the European Society of Cardiology and is also available online in the European Heart Journal.

“We have considered cardiomyopathies across the life course from pediatric to adult,” explained Elena Arbelo, MD, PhD, coordinator of the cardiac genetic diseases and sudden arrhythmic death unit, Hospital Clinic de Barcelona. Dr. Arbelo is first author and one of two chairpersons of the ESC task force that brought the guidelines forward.

Not an update, the ESC guidelines are the first to “include all cardiomyopathy subtypes, and the first time that specific recommendations are made for cardiomyopathies other than hypertrophic cardiomyopathy” (HCM), Dr. Arbelo said.
 

Guidelines organize cardiomyopathy phenotypes

Cardiomyopathy can present at any age. It can have multiple complex etiologies, including genetic predisposition, heart muscle injury caused by disease, or a mix of participating factors. The ESC task force employed several strategies in taking a comprehensive approach to the condition, said Juan Kaski, MD, PhD, professor of pediatric inherited cardiovascular medicine at the University College of London.

“From my point of view, the key innovations include a diagnostic workup that starts with a detailed phenotypic description, including the new phenotype of nondilated left ventricular cardiomyopathy, that then triggers a multiparametric, systematic evaluation,” said Dr. Kaski, cochair of the task force.

As explained in the introduction to the guideline and reiterated by both Dr. Arbelo and Dr. Kaski, the guidelines have been organized around the patient pathway, meaning that focus should be placed on recognizing the presenting phenotype as a critical first step in discerning the underlying etiology and its treatments.

“Central to this approach is not only the individual patient but also the family as a whole,” Dr. Arbelo said. “Clinical findings in relatives are essential for understanding what happens to the patient and vice versa.”
 

Genetic testing in children described

The new guidelines include specific recommendations about genetic testing of children. They also emphasize the value of cardiovascular magnetic resonance (CMR) imaging in the “diagnosis, screening, monitoring, and prognostication” for patients of all ages, according to Dr. Kaski.

“CMR is recommended at the initial evaluation for every patient with cardiomyopathy,” Dr. Arbelo said. It should be “considered” during follow-up and for many other applications, including the evaluation of “genotype-positive but phenotype-negative relatives.”

Etiologic prediction models have been incorporated into the guidelines, including genotyping for dilated cardiomyopathies and nondilated left ventricular cardiomyopathy, said both Dr. Arbelo and Dr. Kaski, interviewed separately. They both indicated that the task force did their best to make the guidelines user friendly.

Each of the recommendations in the guidelines is provided with an evidence-based classification. In order, these are class I (recommended), class IIa (should be considered), class IIb (may be considered), and class III (not recommended).
 

Many symptoms are cardiomyopathy related

Dr. Kaski and Dr. Arbelo both emphasized that the guidelines draw attention to the relationship of cardiomyopathy to common cardiovascular conditions, such as heart failure, arrhythmia, and chest pain. Dr. Kaski pointed out that these are the types of problems commonly encountered by general cardiologists and well as primary care physicians.

In 2014, the ESC published guidelines specific to HCM. The new broader guidelines do not overlook this subtype. According to Dr. Kaski, there have been several innovations in HCM since the previous guidelines, such as when to consider cardiac myosin inhibitors for symptomatic left ventricular outflow tract obstruction.

The ESC guidelines place an emphasis on a “coordinated, systematic, and individualized” care pathway based on a multidisciplinary approach, according to Dr. Arbelo. Although the composition of the interdisciplinary team depends on the individual case, the guidelines recognize a key role for general cardiologists in managing the majority of patients. Suggestions of when to refer challenging cases to expert centers are outlined.
 

32 key messages derived from guidelines

The guidelines include almost 90 pages of recommendations. The task force isolated 32 key messages from 13 sections ranging from descriptions of how the patient pathway is defined to what types of physical activity should be considered for different forms of cardiomyopathy. There is also a section devoted to important gaps in evidence and areas in which there is the most need for further studies.

The guidelines end with a comprehensive list of “what to do” and “what not to do” in the diagnosis and care of cardiomyopathy. These include most of the class I recommendations and summarize some important class III cautions.

“Most of the recommendations in the guideline are new,” the authors wrote in the introduction. Although they acknowledged that they did not attempt to provide detailed recommendations for every cardiomyopathy phenotype, they endeavored to cover general evaluation and management issues supported by relevant evidence.

Dr. Arbelo and Dr. Kaski disclosed no relevant financial relationships.

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

Minimizing atrial pacing does not alter the risk of atrial fibrillation (AF) associated with sinus node dysfunction (SND), suggest results of a trial that randomly assigned patients with SND who had received their first pacemaker implant to one of two pacing programs.

Over 2 years of follow-up with remote monitoring, there was no difference in the primary endpoint of time to first device-detected episode of AF lasting more than 6 minutes, reported Max Brix Kronborg, MD, PhD, department of cardiology, Aarhus University Hospital, Denmark.

The study, DANPACE II, excluded patients with permanent or persistent AF or persistent bradycardia prior to or at the time of enrollment.

The findings were presented at annual congress of the European Society of Cardiology and were published online simultaneously in the European Heart Journal.

The 539 participants in the trial were randomly assigned in a 1:1 ratio to a pacing program of 60 beats/minute with rate-adaptive pacing (DDR-60) or 40 beats/minute without rate-adaptive pacing (DDD-40). All patients were equipped with remote monitoring and were followed for 2 years. Tracings were adjudicated for atrial high-rate episodes by experienced device specialists, Dr. Kronborg said.
 

No difference seen in primary outcome

When graphed, curves for the primary outcome in the two groups were essentially superimposable. For the secondary outcomes of AF lasting more than 6 hours and AF lasting more than 24 hours, there was a modest but progressive separation in the lines favoring the DDR-60 group for both. However, the P value did not approach significance in the first of these endpoints (P = .35) and remained only a trend (P = .08) in the second.

There were no substantial differences in results when patients were stratified by age (> 73 years vs. younger), gender (women represented 50% of patients), PR interval (> 150 milliseconds vs. less), or history of AF prior to study entry; the latter group represented approximately 40% of the trial participants.

There was a between-group difference in the primary composite safety endpoint of syncope and presyncope. By 2 years, 13% of those in the DDR-60 group had experienced one of these safety events, vs. 22% (P = .01) of the DDD-40 group.

The study was not designed to determine a cause for these episodes, but Dr. Kronborg reported that bradycardia was suspected in the majority of cases.
 

Crossovers more common on minimal pacing

Crossovers were permitted, and 26% of patients did so at some point in the trial. Of these, about one-third were switched to the opposite arm in response to syncope. Almost all of the others crossed over because of chronotropic incompetence. The greater crossover rate in the DDD-40 group (23% vs. 3%; P < .001) was highly significant.

Quality of life was measured with the SF36 tool, and physical function was evaluated with the 6-minute walk distance test (6MWD). Results on these measures did not differ significantly between groups. For 6MWD, the mean gain from baseline was 8 m in both groups.

The results of this study are important because they challenge what has been a widely held perception among electrophysiologists, according to Cecilia Linde, MD, PhD, a professor of cardiology at the Karolinska Institute, Stockholm.

“I think many of us involved in pacing thought for many years that minimizing pacing would be beneficial, and this clearly shows it is not,” said Dr. Linde, who was the moderator of the scientific session in which these results were presented.
 

Results appear definitive

The ESC-invited discussant, Jose L. Merino, MD, PhD, director of arrhythmia and electrophysiology research, La Paz University Hospital, Madrid, concurred. He said these results are convincing.

On the basis of these findings, which not only failed to show a benefit but showed in the experimental arm a higher incidence of syncope and chronotropic incompetence, Dr. Merino concluded, “Programming intended to minimize atrial pacing should not be used as routine in unselected patients with SND.”

A trend for protection from DDR-60 over DDD-40 from the longest episodes of AF caught Dr. Merino’s attention, leading him to question whether the optimal rate of pacing might be even higher than 60 beats/minute in SND, but he said that is a separate issue. DANPACE was not powered to examine the effect in long duration episodes.

Ultimately, while Dr. Merino characterized the increased risk of syncope with minimized pacing as “an important finding” in regard to dissuading clinicians to pursue this strategy, he said that the underlying question of the DANPACE trial remains unanswered.

Pacing remains “a treatment of choice” in SND, but further investigation is needed “about the optimal pacing rate to minimize AF and syncope” in this population, he said.

Dr. Kronborg reports a financial relationship with Abbott. Dr. Linde reports financial relationships with Cardio 3, Medtronic, St. Jude, and Vifor. Dr. Merino reports financial relationships with Abbott, Medtronic, and Microport.

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

Minimizing atrial pacing does not alter the risk of atrial fibrillation (AF) associated with sinus node dysfunction (SND), suggest results of a trial that randomly assigned patients with SND who had received their first pacemaker implant to one of two pacing programs.

Over 2 years of follow-up with remote monitoring, there was no difference in the primary endpoint of time to first device-detected episode of AF lasting more than 6 minutes, reported Max Brix Kronborg, MD, PhD, department of cardiology, Aarhus University Hospital, Denmark.

The study, DANPACE II, excluded patients with permanent or persistent AF or persistent bradycardia prior to or at the time of enrollment.

The findings were presented at annual congress of the European Society of Cardiology and were published online simultaneously in the European Heart Journal.

The 539 participants in the trial were randomly assigned in a 1:1 ratio to a pacing program of 60 beats/minute with rate-adaptive pacing (DDR-60) or 40 beats/minute without rate-adaptive pacing (DDD-40). All patients were equipped with remote monitoring and were followed for 2 years. Tracings were adjudicated for atrial high-rate episodes by experienced device specialists, Dr. Kronborg said.
 

No difference seen in primary outcome

When graphed, curves for the primary outcome in the two groups were essentially superimposable. For the secondary outcomes of AF lasting more than 6 hours and AF lasting more than 24 hours, there was a modest but progressive separation in the lines favoring the DDR-60 group for both. However, the P value did not approach significance in the first of these endpoints (P = .35) and remained only a trend (P = .08) in the second.

There were no substantial differences in results when patients were stratified by age (> 73 years vs. younger), gender (women represented 50% of patients), PR interval (> 150 milliseconds vs. less), or history of AF prior to study entry; the latter group represented approximately 40% of the trial participants.

There was a between-group difference in the primary composite safety endpoint of syncope and presyncope. By 2 years, 13% of those in the DDR-60 group had experienced one of these safety events, vs. 22% (P = .01) of the DDD-40 group.

The study was not designed to determine a cause for these episodes, but Dr. Kronborg reported that bradycardia was suspected in the majority of cases.
 

Crossovers more common on minimal pacing

Crossovers were permitted, and 26% of patients did so at some point in the trial. Of these, about one-third were switched to the opposite arm in response to syncope. Almost all of the others crossed over because of chronotropic incompetence. The greater crossover rate in the DDD-40 group (23% vs. 3%; P < .001) was highly significant.

Quality of life was measured with the SF36 tool, and physical function was evaluated with the 6-minute walk distance test (6MWD). Results on these measures did not differ significantly between groups. For 6MWD, the mean gain from baseline was 8 m in both groups.

The results of this study are important because they challenge what has been a widely held perception among electrophysiologists, according to Cecilia Linde, MD, PhD, a professor of cardiology at the Karolinska Institute, Stockholm.

“I think many of us involved in pacing thought for many years that minimizing pacing would be beneficial, and this clearly shows it is not,” said Dr. Linde, who was the moderator of the scientific session in which these results were presented.
 

Results appear definitive

The ESC-invited discussant, Jose L. Merino, MD, PhD, director of arrhythmia and electrophysiology research, La Paz University Hospital, Madrid, concurred. He said these results are convincing.

On the basis of these findings, which not only failed to show a benefit but showed in the experimental arm a higher incidence of syncope and chronotropic incompetence, Dr. Merino concluded, “Programming intended to minimize atrial pacing should not be used as routine in unselected patients with SND.”

A trend for protection from DDR-60 over DDD-40 from the longest episodes of AF caught Dr. Merino’s attention, leading him to question whether the optimal rate of pacing might be even higher than 60 beats/minute in SND, but he said that is a separate issue. DANPACE was not powered to examine the effect in long duration episodes.

Ultimately, while Dr. Merino characterized the increased risk of syncope with minimized pacing as “an important finding” in regard to dissuading clinicians to pursue this strategy, he said that the underlying question of the DANPACE trial remains unanswered.

Pacing remains “a treatment of choice” in SND, but further investigation is needed “about the optimal pacing rate to minimize AF and syncope” in this population, he said.

Dr. Kronborg reports a financial relationship with Abbott. Dr. Linde reports financial relationships with Cardio 3, Medtronic, St. Jude, and Vifor. Dr. Merino reports financial relationships with Abbott, Medtronic, and Microport.

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

Minimizing atrial pacing does not alter the risk of atrial fibrillation (AF) associated with sinus node dysfunction (SND), suggest results of a trial that randomly assigned patients with SND who had received their first pacemaker implant to one of two pacing programs.

Over 2 years of follow-up with remote monitoring, there was no difference in the primary endpoint of time to first device-detected episode of AF lasting more than 6 minutes, reported Max Brix Kronborg, MD, PhD, department of cardiology, Aarhus University Hospital, Denmark.

The study, DANPACE II, excluded patients with permanent or persistent AF or persistent bradycardia prior to or at the time of enrollment.

The findings were presented at annual congress of the European Society of Cardiology and were published online simultaneously in the European Heart Journal.

The 539 participants in the trial were randomly assigned in a 1:1 ratio to a pacing program of 60 beats/minute with rate-adaptive pacing (DDR-60) or 40 beats/minute without rate-adaptive pacing (DDD-40). All patients were equipped with remote monitoring and were followed for 2 years. Tracings were adjudicated for atrial high-rate episodes by experienced device specialists, Dr. Kronborg said.
 

No difference seen in primary outcome

When graphed, curves for the primary outcome in the two groups were essentially superimposable. For the secondary outcomes of AF lasting more than 6 hours and AF lasting more than 24 hours, there was a modest but progressive separation in the lines favoring the DDR-60 group for both. However, the P value did not approach significance in the first of these endpoints (P = .35) and remained only a trend (P = .08) in the second.

There were no substantial differences in results when patients were stratified by age (> 73 years vs. younger), gender (women represented 50% of patients), PR interval (> 150 milliseconds vs. less), or history of AF prior to study entry; the latter group represented approximately 40% of the trial participants.

There was a between-group difference in the primary composite safety endpoint of syncope and presyncope. By 2 years, 13% of those in the DDR-60 group had experienced one of these safety events, vs. 22% (P = .01) of the DDD-40 group.

The study was not designed to determine a cause for these episodes, but Dr. Kronborg reported that bradycardia was suspected in the majority of cases.
 

Crossovers more common on minimal pacing

Crossovers were permitted, and 26% of patients did so at some point in the trial. Of these, about one-third were switched to the opposite arm in response to syncope. Almost all of the others crossed over because of chronotropic incompetence. The greater crossover rate in the DDD-40 group (23% vs. 3%; P < .001) was highly significant.

Quality of life was measured with the SF36 tool, and physical function was evaluated with the 6-minute walk distance test (6MWD). Results on these measures did not differ significantly between groups. For 6MWD, the mean gain from baseline was 8 m in both groups.

The results of this study are important because they challenge what has been a widely held perception among electrophysiologists, according to Cecilia Linde, MD, PhD, a professor of cardiology at the Karolinska Institute, Stockholm.

“I think many of us involved in pacing thought for many years that minimizing pacing would be beneficial, and this clearly shows it is not,” said Dr. Linde, who was the moderator of the scientific session in which these results were presented.
 

Results appear definitive

The ESC-invited discussant, Jose L. Merino, MD, PhD, director of arrhythmia and electrophysiology research, La Paz University Hospital, Madrid, concurred. He said these results are convincing.

On the basis of these findings, which not only failed to show a benefit but showed in the experimental arm a higher incidence of syncope and chronotropic incompetence, Dr. Merino concluded, “Programming intended to minimize atrial pacing should not be used as routine in unselected patients with SND.”

A trend for protection from DDR-60 over DDD-40 from the longest episodes of AF caught Dr. Merino’s attention, leading him to question whether the optimal rate of pacing might be even higher than 60 beats/minute in SND, but he said that is a separate issue. DANPACE was not powered to examine the effect in long duration episodes.

Ultimately, while Dr. Merino characterized the increased risk of syncope with minimized pacing as “an important finding” in regard to dissuading clinicians to pursue this strategy, he said that the underlying question of the DANPACE trial remains unanswered.

Pacing remains “a treatment of choice” in SND, but further investigation is needed “about the optimal pacing rate to minimize AF and syncope” in this population, he said.

Dr. Kronborg reports a financial relationship with Abbott. Dr. Linde reports financial relationships with Cardio 3, Medtronic, St. Jude, and Vifor. Dr. Merino reports financial relationships with Abbott, Medtronic, and Microport.

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

When added to guideline-directed therapies for heart failure with reduced ejection fraction (HFrEF), a traditional Chinese medicine called qiliqiangxin reduced the composite endpoint of cardiovascular death and heart failure hospitalization by more than 20%, results of a large placebo-controlled trial show.

“The risk reductions in both cardiovascular death and heart failure hospitalization were substantial, clinically important, and consistent across all subgroups,” reported Xinli Li, MD, PhD, First Affiliated Hospital, Nanjing Medical University, China.

Qiliqiangxin, a commonly used therapy in China for cardiovascular disease, is not a single chemical entity but a treatment composed of 11 plant-based substances that together are associated with diuretic effects, vasodilation, and “cardiotonic” activity, Dr. Li said. He also cited studies showing an upregulation effect on peroxisome proliferator-activated receptor gamma coactivator 1-beta (PGC1-beta).

The results were presented at the annual congress of the European Society of Cardiology.
 

Hard endpoints pursued in rigorous design

There have been numerous studies of qiliqiangxin for cardiovascular diseases, including a double-blind study that associated this agent with a greater than 30% reduction in the surrogate endpoint of N-terminal pro–B-type natriuretic peptide (NT-proBNP).

In the newly completed multicenter trial, called QUEST, the goal was to determine whether this therapy could reduce hard endpoints relative to placebo in a rigorously conducted trial enrolling patients receiving an optimized triple-therapy heart failure regimen.

Few patients in the study received a sodium glucose cotransporter-2 (SGLT-2 inhibitor), which was not a standard at the time the study was designed but is now part of the quadruple guideline-directed medical therapy in most European and North American guidelines.

In this trial, 3,119 patients were randomly assigned at 133 centers in China to take four capsules of qiliqiangxin or placebo three times per day. At a median follow-up of 18.3 months, outcomes were evaluable in nearly all 1,561 patients randomly assigned to the experimental therapy and 1,555 patients randomly assigned to placebo.

The key inclusion criteria were a left ventricular ejection fraction of 40% or less and a serum NT-proBNP level of at least 450 pg/mL. Patients in New York Heart Association class IV heart failure were excluded.

At enrollment, more than 80% of patients in both arms were receiving a renin-angiotensin system (RAS) inhibitor (angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, or angiotensin receptor neprilysin inhibitor), more than 80% were receiving a mineralocorticoid receptor antagonist, and more than 85% were receiving a beta-blocker.
 

Death and hospitalization reduced 22%

By hazard ratio, the primary composite endpoint of CV death and heart failure hospitalization was reduced by 22% relative to placebo (HR, 0.78; P < .001). When evaluated separately, the relative reductions in these respective endpoints were 17% (HR, 0.83; P = .045) and 24% (HR, 0.76; P = .002).

The risk reduction was robust (HR, 0.76; P < .001) in patients with an ischemic cause but nonsignificant in those without (HR, 0.92; P = .575). A significant benefit was sustained in patients receiving an angiotensin receptor neprilysin inhibitor (HR, 0.84; P = .041), as well as those who did not receive this class of drug (HR, 0.77; P = .012).

However, the benefit of qiliqiangxin among patients receiving all components of guideline-directed triple therapy (RAS inhibitor, beta-blocker, and mineralocorticoid antagonist) was only a trend (HR, 0.86; P = .079).

All-cause mortality, a secondary endpoint, was lower among patients randomly assigned to qiliqiangxin than to those assigned to placebo, but this difference fell just short of statistical significance (14.21% vs. 16.85%; P = .058).

Qiliqiangxin was well tolerated. The proportion of patients with a serious adverse event was numerically lower with qiliqiangxin than with placebo (17.43% vs. 19.74%), whereas discontinuations associated with an adverse event were numerically higher in the qiliqiangxin group (1.03% vs. 0.58%), albeit still very low in both study arms.
 

Overlap of drug benefits suspected

Given the safety of this drug and its highly significant reduction in a composite endpoint used in other major HFrEF trials, the ESC-invited discussant, Carolyn S.P. Lam, MBBS, PhD, National Heart Centre, Singapore, called the outcome “remarkable” and a validation for “the millions of people” who are already taking qiliqiangxin in China and other Asian countries.

Using the DAPA-HF trial as a point of reference, Dr. Lam noted that relative reduction in the composite endpoint of cardiovascular death for the SGLT-2 inhibitor dapagliflozin relative to placebo on top of triple guideline-directed medical therapy was lower (17% vs. 24%), but there were significant reductions in each of the components, as well as a nonsignificant signal of a mortality benefit.

However, Dr. Lam pointed out that there does seem to be more of an overlap for the benefits of qiliqiangxin than dapagliflozin relative to other components of triple therapy based on the lower rate of benefit when patients were optimized on triple therapy.

“The subgroup analysis [of this study] is very important,” Dr. Lam said. Qiliqiangxin may be best in patients who cannot take one or more of the components of triple therapy, she suggested, even though she called for further studies to test this theory. She also cautioned that the pill burden of four capsules taken three times per day might be onerous for some patients.

Of the many questions still to be answered, Dr. Lam noted that the low rate of enrollment for patients (< 10%) taking SGLT-2 inhibitors makes the contribution of qiliqiangxin unclear among those receiving the current standard of quadruple guideline-directed medical therapy.

She also suggested that it will be important to dissect the relative contribution of the different active ingredients of qiliqiangxin.

“This is not a purified compound that we are used to in Western medicine,” Dr. Lam said. While she praised the study as “scientifically rigorous” and indicated that the results support a clinical benefit from qiliqiangxin, she thinks an exploration of the mechanism or mechanisms of benefit is a next step in understanding where this therapy fits in HFrEF management.

Dr. Li reports financial relationships with AstraZeneca, Bayer, Novartis, Roche, and Yiling. Dr. Lam reports financial relationships with more than 25 pharmaceutical or device manufacturers, many of which produce therapies for heart failure, as well as with Medscape/WebMD Global LLC. The study was supported by the Chinese National Key Research and Development Project and Yiling Pharmaceuticals.

A version of this article appeared on Medscape.com.

When added to guideline-directed therapies for heart failure with reduced ejection fraction (HFrEF), a traditional Chinese medicine called qiliqiangxin reduced the composite endpoint of cardiovascular death and heart failure hospitalization by more than 20%, results of a large placebo-controlled trial show.

“The risk reductions in both cardiovascular death and heart failure hospitalization were substantial, clinically important, and consistent across all subgroups,” reported Xinli Li, MD, PhD, First Affiliated Hospital, Nanjing Medical University, China.

Qiliqiangxin, a commonly used therapy in China for cardiovascular disease, is not a single chemical entity but a treatment composed of 11 plant-based substances that together are associated with diuretic effects, vasodilation, and “cardiotonic” activity, Dr. Li said. He also cited studies showing an upregulation effect on peroxisome proliferator-activated receptor gamma coactivator 1-beta (PGC1-beta).

The results were presented at the annual congress of the European Society of Cardiology.
 

Hard endpoints pursued in rigorous design

There have been numerous studies of qiliqiangxin for cardiovascular diseases, including a double-blind study that associated this agent with a greater than 30% reduction in the surrogate endpoint of N-terminal pro–B-type natriuretic peptide (NT-proBNP).

In the newly completed multicenter trial, called QUEST, the goal was to determine whether this therapy could reduce hard endpoints relative to placebo in a rigorously conducted trial enrolling patients receiving an optimized triple-therapy heart failure regimen.

Few patients in the study received a sodium glucose cotransporter-2 (SGLT-2 inhibitor), which was not a standard at the time the study was designed but is now part of the quadruple guideline-directed medical therapy in most European and North American guidelines.

In this trial, 3,119 patients were randomly assigned at 133 centers in China to take four capsules of qiliqiangxin or placebo three times per day. At a median follow-up of 18.3 months, outcomes were evaluable in nearly all 1,561 patients randomly assigned to the experimental therapy and 1,555 patients randomly assigned to placebo.

The key inclusion criteria were a left ventricular ejection fraction of 40% or less and a serum NT-proBNP level of at least 450 pg/mL. Patients in New York Heart Association class IV heart failure were excluded.

At enrollment, more than 80% of patients in both arms were receiving a renin-angiotensin system (RAS) inhibitor (angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, or angiotensin receptor neprilysin inhibitor), more than 80% were receiving a mineralocorticoid receptor antagonist, and more than 85% were receiving a beta-blocker.
 

Death and hospitalization reduced 22%

By hazard ratio, the primary composite endpoint of CV death and heart failure hospitalization was reduced by 22% relative to placebo (HR, 0.78; P < .001). When evaluated separately, the relative reductions in these respective endpoints were 17% (HR, 0.83; P = .045) and 24% (HR, 0.76; P = .002).

The risk reduction was robust (HR, 0.76; P < .001) in patients with an ischemic cause but nonsignificant in those without (HR, 0.92; P = .575). A significant benefit was sustained in patients receiving an angiotensin receptor neprilysin inhibitor (HR, 0.84; P = .041), as well as those who did not receive this class of drug (HR, 0.77; P = .012).

However, the benefit of qiliqiangxin among patients receiving all components of guideline-directed triple therapy (RAS inhibitor, beta-blocker, and mineralocorticoid antagonist) was only a trend (HR, 0.86; P = .079).

All-cause mortality, a secondary endpoint, was lower among patients randomly assigned to qiliqiangxin than to those assigned to placebo, but this difference fell just short of statistical significance (14.21% vs. 16.85%; P = .058).

Qiliqiangxin was well tolerated. The proportion of patients with a serious adverse event was numerically lower with qiliqiangxin than with placebo (17.43% vs. 19.74%), whereas discontinuations associated with an adverse event were numerically higher in the qiliqiangxin group (1.03% vs. 0.58%), albeit still very low in both study arms.
 

Overlap of drug benefits suspected

Given the safety of this drug and its highly significant reduction in a composite endpoint used in other major HFrEF trials, the ESC-invited discussant, Carolyn S.P. Lam, MBBS, PhD, National Heart Centre, Singapore, called the outcome “remarkable” and a validation for “the millions of people” who are already taking qiliqiangxin in China and other Asian countries.

Using the DAPA-HF trial as a point of reference, Dr. Lam noted that relative reduction in the composite endpoint of cardiovascular death for the SGLT-2 inhibitor dapagliflozin relative to placebo on top of triple guideline-directed medical therapy was lower (17% vs. 24%), but there were significant reductions in each of the components, as well as a nonsignificant signal of a mortality benefit.

However, Dr. Lam pointed out that there does seem to be more of an overlap for the benefits of qiliqiangxin than dapagliflozin relative to other components of triple therapy based on the lower rate of benefit when patients were optimized on triple therapy.

“The subgroup analysis [of this study] is very important,” Dr. Lam said. Qiliqiangxin may be best in patients who cannot take one or more of the components of triple therapy, she suggested, even though she called for further studies to test this theory. She also cautioned that the pill burden of four capsules taken three times per day might be onerous for some patients.

Of the many questions still to be answered, Dr. Lam noted that the low rate of enrollment for patients (< 10%) taking SGLT-2 inhibitors makes the contribution of qiliqiangxin unclear among those receiving the current standard of quadruple guideline-directed medical therapy.

She also suggested that it will be important to dissect the relative contribution of the different active ingredients of qiliqiangxin.

“This is not a purified compound that we are used to in Western medicine,” Dr. Lam said. While she praised the study as “scientifically rigorous” and indicated that the results support a clinical benefit from qiliqiangxin, she thinks an exploration of the mechanism or mechanisms of benefit is a next step in understanding where this therapy fits in HFrEF management.

Dr. Li reports financial relationships with AstraZeneca, Bayer, Novartis, Roche, and Yiling. Dr. Lam reports financial relationships with more than 25 pharmaceutical or device manufacturers, many of which produce therapies for heart failure, as well as with Medscape/WebMD Global LLC. The study was supported by the Chinese National Key Research and Development Project and Yiling Pharmaceuticals.

A version of this article appeared on Medscape.com.

When added to guideline-directed therapies for heart failure with reduced ejection fraction (HFrEF), a traditional Chinese medicine called qiliqiangxin reduced the composite endpoint of cardiovascular death and heart failure hospitalization by more than 20%, results of a large placebo-controlled trial show.

“The risk reductions in both cardiovascular death and heart failure hospitalization were substantial, clinically important, and consistent across all subgroups,” reported Xinli Li, MD, PhD, First Affiliated Hospital, Nanjing Medical University, China.

Qiliqiangxin, a commonly used therapy in China for cardiovascular disease, is not a single chemical entity but a treatment composed of 11 plant-based substances that together are associated with diuretic effects, vasodilation, and “cardiotonic” activity, Dr. Li said. He also cited studies showing an upregulation effect on peroxisome proliferator-activated receptor gamma coactivator 1-beta (PGC1-beta).

The results were presented at the annual congress of the European Society of Cardiology.
 

Hard endpoints pursued in rigorous design

There have been numerous studies of qiliqiangxin for cardiovascular diseases, including a double-blind study that associated this agent with a greater than 30% reduction in the surrogate endpoint of N-terminal pro–B-type natriuretic peptide (NT-proBNP).

In the newly completed multicenter trial, called QUEST, the goal was to determine whether this therapy could reduce hard endpoints relative to placebo in a rigorously conducted trial enrolling patients receiving an optimized triple-therapy heart failure regimen.

Few patients in the study received a sodium glucose cotransporter-2 (SGLT-2 inhibitor), which was not a standard at the time the study was designed but is now part of the quadruple guideline-directed medical therapy in most European and North American guidelines.

In this trial, 3,119 patients were randomly assigned at 133 centers in China to take four capsules of qiliqiangxin or placebo three times per day. At a median follow-up of 18.3 months, outcomes were evaluable in nearly all 1,561 patients randomly assigned to the experimental therapy and 1,555 patients randomly assigned to placebo.

The key inclusion criteria were a left ventricular ejection fraction of 40% or less and a serum NT-proBNP level of at least 450 pg/mL. Patients in New York Heart Association class IV heart failure were excluded.

At enrollment, more than 80% of patients in both arms were receiving a renin-angiotensin system (RAS) inhibitor (angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, or angiotensin receptor neprilysin inhibitor), more than 80% were receiving a mineralocorticoid receptor antagonist, and more than 85% were receiving a beta-blocker.
 

Death and hospitalization reduced 22%

By hazard ratio, the primary composite endpoint of CV death and heart failure hospitalization was reduced by 22% relative to placebo (HR, 0.78; P < .001). When evaluated separately, the relative reductions in these respective endpoints were 17% (HR, 0.83; P = .045) and 24% (HR, 0.76; P = .002).

The risk reduction was robust (HR, 0.76; P < .001) in patients with an ischemic cause but nonsignificant in those without (HR, 0.92; P = .575). A significant benefit was sustained in patients receiving an angiotensin receptor neprilysin inhibitor (HR, 0.84; P = .041), as well as those who did not receive this class of drug (HR, 0.77; P = .012).

However, the benefit of qiliqiangxin among patients receiving all components of guideline-directed triple therapy (RAS inhibitor, beta-blocker, and mineralocorticoid antagonist) was only a trend (HR, 0.86; P = .079).

All-cause mortality, a secondary endpoint, was lower among patients randomly assigned to qiliqiangxin than to those assigned to placebo, but this difference fell just short of statistical significance (14.21% vs. 16.85%; P = .058).

Qiliqiangxin was well tolerated. The proportion of patients with a serious adverse event was numerically lower with qiliqiangxin than with placebo (17.43% vs. 19.74%), whereas discontinuations associated with an adverse event were numerically higher in the qiliqiangxin group (1.03% vs. 0.58%), albeit still very low in both study arms.
 

Overlap of drug benefits suspected

Given the safety of this drug and its highly significant reduction in a composite endpoint used in other major HFrEF trials, the ESC-invited discussant, Carolyn S.P. Lam, MBBS, PhD, National Heart Centre, Singapore, called the outcome “remarkable” and a validation for “the millions of people” who are already taking qiliqiangxin in China and other Asian countries.

Using the DAPA-HF trial as a point of reference, Dr. Lam noted that relative reduction in the composite endpoint of cardiovascular death for the SGLT-2 inhibitor dapagliflozin relative to placebo on top of triple guideline-directed medical therapy was lower (17% vs. 24%), but there were significant reductions in each of the components, as well as a nonsignificant signal of a mortality benefit.

However, Dr. Lam pointed out that there does seem to be more of an overlap for the benefits of qiliqiangxin than dapagliflozin relative to other components of triple therapy based on the lower rate of benefit when patients were optimized on triple therapy.

“The subgroup analysis [of this study] is very important,” Dr. Lam said. Qiliqiangxin may be best in patients who cannot take one or more of the components of triple therapy, she suggested, even though she called for further studies to test this theory. She also cautioned that the pill burden of four capsules taken three times per day might be onerous for some patients.

Of the many questions still to be answered, Dr. Lam noted that the low rate of enrollment for patients (< 10%) taking SGLT-2 inhibitors makes the contribution of qiliqiangxin unclear among those receiving the current standard of quadruple guideline-directed medical therapy.

She also suggested that it will be important to dissect the relative contribution of the different active ingredients of qiliqiangxin.

“This is not a purified compound that we are used to in Western medicine,” Dr. Lam said. While she praised the study as “scientifically rigorous” and indicated that the results support a clinical benefit from qiliqiangxin, she thinks an exploration of the mechanism or mechanisms of benefit is a next step in understanding where this therapy fits in HFrEF management.

Dr. Li reports financial relationships with AstraZeneca, Bayer, Novartis, Roche, and Yiling. Dr. Lam reports financial relationships with more than 25 pharmaceutical or device manufacturers, many of which produce therapies for heart failure, as well as with Medscape/WebMD Global LLC. The study was supported by the Chinese National Key Research and Development Project and Yiling Pharmaceuticals.

A version of this article appeared on Medscape.com.