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Sustained reductions in Lp(a) achieved with novel siRNA drug
In an early phase multicenter clinical study,
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,
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,
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.
FROM AHA 2023
Dropping aspirin cuts bleeding in LVAD patients: ARIES-HM3
PHILADELPHIA – particularly if it’s a newer device that does not use the centrifugal- or continuous-flow pump technology of conventional LVADs, new randomized results suggest.
“We’ve always thought that somehow aspirin prevents stroke and prevents clotting and that it’s anti-inflammatory, and what we found in ARIES was the exact opposite,” said Mandeep Mehra, MD, of Brigham and Women’s Hospital Heart and Vascular Center and Harvard Medical School, both in Boston, who reported results of the ARIES-HM3 trial of the HeartMate 3 LVAD, a device that uses a fully magnetically levitated rotor to maintain blood flow.
ARIES-HM3 randomly assigned 589 patients who received the HeartMate 3 device to vitamin K therapy with aspirin or to placebo. Dr. Mehra said it was the first international trial to conclusively evaluate medical therapy in patients who get an LVAD.
Unexpected findings
“To be honest with you, we set this up as a safety study to see if we could eliminate aspirin,” Dr. Mehra said in an interview. “We didn’t expect that the bleeding rates would decrease by 34% and that gastrointestinal bleeding in particular would decrease by 40%. We didn’t expect that it would nearly halve the days spent in the hospital, and we didn’t expect that the cost of care would decrease by 40%.”
Dr. Mehra reported the results at the annual scientific sessions of the American Heart Association. They were published simultaneously online in JAMA.
The researchers found that 74% of patients in the placebo group met the primary endpoint of being alive and not having any hemocompatibility events at 12 months vs 68% of the aspirin patients. The rate of nonsurgical bleeding events was 30% in the placebo group versus 42.4% in the aspirin patients. The rates of GI bleeding were 13% and 21.6% in the respective groups.
In his talk, Dr. Mehra noted the placebo group spent 47% fewer days in the hospital for bleeding, with hospitalization costs 41% lower than the aspirin group.
“We are very quick to throw things as deemed medical therapy at patients and this study outcome should give us pause that not everything we do may be right, and that we need to start building a stronger evidence base in medical therapy for what we do with patients that are on device support,” Dr. Mehra said.
Shift of focus to therapy
The study’s focus on aspirin therapy may be as significant as its evaluation of the HeartMate 3 LVAD, discussant Eric David Adler, MD, a cardiologist and section head of heart transplant at the University of California, San Diego, said in an interview.
“We focus so much on the device,” he said. “It’s like a set-it-and-forget-it kind of thing and we’re surprised that we see complications because we haven’t put a lot of effort into the medical therapy component.”
But he credited this study for doing just that, adding that it can serve as a model for future studies of LVADs, although such studies can face hurdles. “These studies are not trivial to accomplish,” he said. “Placebo medical therapy studies are very expensive, but I think this is a mandate for doing more studies. This is just the tip of the iceberg.”
Additionally, evaluating hospital stays in LVAD studies “is a really important endpoint,” Dr. Adler said.
“For me, one of the key things that we don’t think about enough is that lowering days in the hospital is a really big deal,” he said. “No one wants to spend time in the hospital, so anything we can do to lower the amount of hospital days is real impactful.”
Abbott funded and sponsored the ARIES-HM3 trial. Dr. Mehra disclosed relationships with Abbott, Moderna, Natera, Transmedics, Paragonix, NupulseCV, FineHeart, and Leviticus. Dr. Adler has disclosed no relevant financial relationships.
PHILADELPHIA – particularly if it’s a newer device that does not use the centrifugal- or continuous-flow pump technology of conventional LVADs, new randomized results suggest.
“We’ve always thought that somehow aspirin prevents stroke and prevents clotting and that it’s anti-inflammatory, and what we found in ARIES was the exact opposite,” said Mandeep Mehra, MD, of Brigham and Women’s Hospital Heart and Vascular Center and Harvard Medical School, both in Boston, who reported results of the ARIES-HM3 trial of the HeartMate 3 LVAD, a device that uses a fully magnetically levitated rotor to maintain blood flow.
ARIES-HM3 randomly assigned 589 patients who received the HeartMate 3 device to vitamin K therapy with aspirin or to placebo. Dr. Mehra said it was the first international trial to conclusively evaluate medical therapy in patients who get an LVAD.
Unexpected findings
“To be honest with you, we set this up as a safety study to see if we could eliminate aspirin,” Dr. Mehra said in an interview. “We didn’t expect that the bleeding rates would decrease by 34% and that gastrointestinal bleeding in particular would decrease by 40%. We didn’t expect that it would nearly halve the days spent in the hospital, and we didn’t expect that the cost of care would decrease by 40%.”
Dr. Mehra reported the results at the annual scientific sessions of the American Heart Association. They were published simultaneously online in JAMA.
The researchers found that 74% of patients in the placebo group met the primary endpoint of being alive and not having any hemocompatibility events at 12 months vs 68% of the aspirin patients. The rate of nonsurgical bleeding events was 30% in the placebo group versus 42.4% in the aspirin patients. The rates of GI bleeding were 13% and 21.6% in the respective groups.
In his talk, Dr. Mehra noted the placebo group spent 47% fewer days in the hospital for bleeding, with hospitalization costs 41% lower than the aspirin group.
“We are very quick to throw things as deemed medical therapy at patients and this study outcome should give us pause that not everything we do may be right, and that we need to start building a stronger evidence base in medical therapy for what we do with patients that are on device support,” Dr. Mehra said.
Shift of focus to therapy
The study’s focus on aspirin therapy may be as significant as its evaluation of the HeartMate 3 LVAD, discussant Eric David Adler, MD, a cardiologist and section head of heart transplant at the University of California, San Diego, said in an interview.
“We focus so much on the device,” he said. “It’s like a set-it-and-forget-it kind of thing and we’re surprised that we see complications because we haven’t put a lot of effort into the medical therapy component.”
But he credited this study for doing just that, adding that it can serve as a model for future studies of LVADs, although such studies can face hurdles. “These studies are not trivial to accomplish,” he said. “Placebo medical therapy studies are very expensive, but I think this is a mandate for doing more studies. This is just the tip of the iceberg.”
Additionally, evaluating hospital stays in LVAD studies “is a really important endpoint,” Dr. Adler said.
“For me, one of the key things that we don’t think about enough is that lowering days in the hospital is a really big deal,” he said. “No one wants to spend time in the hospital, so anything we can do to lower the amount of hospital days is real impactful.”
Abbott funded and sponsored the ARIES-HM3 trial. Dr. Mehra disclosed relationships with Abbott, Moderna, Natera, Transmedics, Paragonix, NupulseCV, FineHeart, and Leviticus. Dr. Adler has disclosed no relevant financial relationships.
PHILADELPHIA – particularly if it’s a newer device that does not use the centrifugal- or continuous-flow pump technology of conventional LVADs, new randomized results suggest.
“We’ve always thought that somehow aspirin prevents stroke and prevents clotting and that it’s anti-inflammatory, and what we found in ARIES was the exact opposite,” said Mandeep Mehra, MD, of Brigham and Women’s Hospital Heart and Vascular Center and Harvard Medical School, both in Boston, who reported results of the ARIES-HM3 trial of the HeartMate 3 LVAD, a device that uses a fully magnetically levitated rotor to maintain blood flow.
ARIES-HM3 randomly assigned 589 patients who received the HeartMate 3 device to vitamin K therapy with aspirin or to placebo. Dr. Mehra said it was the first international trial to conclusively evaluate medical therapy in patients who get an LVAD.
Unexpected findings
“To be honest with you, we set this up as a safety study to see if we could eliminate aspirin,” Dr. Mehra said in an interview. “We didn’t expect that the bleeding rates would decrease by 34% and that gastrointestinal bleeding in particular would decrease by 40%. We didn’t expect that it would nearly halve the days spent in the hospital, and we didn’t expect that the cost of care would decrease by 40%.”
Dr. Mehra reported the results at the annual scientific sessions of the American Heart Association. They were published simultaneously online in JAMA.
The researchers found that 74% of patients in the placebo group met the primary endpoint of being alive and not having any hemocompatibility events at 12 months vs 68% of the aspirin patients. The rate of nonsurgical bleeding events was 30% in the placebo group versus 42.4% in the aspirin patients. The rates of GI bleeding were 13% and 21.6% in the respective groups.
In his talk, Dr. Mehra noted the placebo group spent 47% fewer days in the hospital for bleeding, with hospitalization costs 41% lower than the aspirin group.
“We are very quick to throw things as deemed medical therapy at patients and this study outcome should give us pause that not everything we do may be right, and that we need to start building a stronger evidence base in medical therapy for what we do with patients that are on device support,” Dr. Mehra said.
Shift of focus to therapy
The study’s focus on aspirin therapy may be as significant as its evaluation of the HeartMate 3 LVAD, discussant Eric David Adler, MD, a cardiologist and section head of heart transplant at the University of California, San Diego, said in an interview.
“We focus so much on the device,” he said. “It’s like a set-it-and-forget-it kind of thing and we’re surprised that we see complications because we haven’t put a lot of effort into the medical therapy component.”
But he credited this study for doing just that, adding that it can serve as a model for future studies of LVADs, although such studies can face hurdles. “These studies are not trivial to accomplish,” he said. “Placebo medical therapy studies are very expensive, but I think this is a mandate for doing more studies. This is just the tip of the iceberg.”
Additionally, evaluating hospital stays in LVAD studies “is a really important endpoint,” Dr. Adler said.
“For me, one of the key things that we don’t think about enough is that lowering days in the hospital is a really big deal,” he said. “No one wants to spend time in the hospital, so anything we can do to lower the amount of hospital days is real impactful.”
Abbott funded and sponsored the ARIES-HM3 trial. Dr. Mehra disclosed relationships with Abbott, Moderna, Natera, Transmedics, Paragonix, NupulseCV, FineHeart, and Leviticus. Dr. Adler has disclosed no relevant financial relationships.
AT AHA 2023
CPPD nomenclature is sore subject for gout group
LA JOLLA, CALIF. – Twelve years ago, an international task force of the European Alliance of Associations for Rheumatology (EULAR) released recommendations regarding nomenclature in calcium pyrophosphate deposition disease (CPPD), aiming to standardize the way the condition is described. “Pseudogout” was out, and “acute CPP crystal arthritis” was in, and a confusing array of multi-named phenotypes gained specific labels.
Since 2011, the nomenclature guidelines have been cited hundreds of times, but a new report finds that the medical literature mostly hasn’t followed the recommendations. The findings were released at the annual research symposium of the Gout, Hyperuricemia, and Crystal Associated Disease Network (G-CAN), which is taking another stab at overhauling CPPD nomenclature.
“The objective is to uniform and standardize the labels of the disease, the disease elements, and the clinical states,” rheumatologist Charlotte Jauffret, MD, of the Catholic University of Lille (France), said in a presentation. CPPD is a widely underdiagnosed disease that’s worth the same efforts to standardize nomenclature as occurred in gout, she said.
As Dr. Jauffret explained, CPPD has a diversity of phenotypes in asymptomatic, acute, and chronic forms that pose challenges to diagnosis. “The same terms are used to depict different concepts, and some disease elements are depicted through different names,” she said.
Among other suggestions, the 2011 EULAR recommendations suggested that rheumatologists use the terms chronic CPP crystal inflammatory arthritis instead of “pseudo-rheumatoid arthritis,” osteoarthritis with CPPD, instead of “pseudo-osteoarthritis,” and severe joint degeneration instead of “pseudo-neuropathic joint disease.”
Later reports noted that terms such as CPPD and chondrocalcinosis are still wrongly used interchangeably and called for an international consensus on nomenclature, Dr. Jauffret said.
For the new report, Dr. Jauffret and colleagues examined 985 articles from 2000-2022. The guidelines were often not followed even after the release of the recommendations.
For example, 49% of relevant papers used the label “pseudogout” before 2011, and 43% did afterward. A total of 34% of relevant papers described CPPD as chondrocalcinosis prior to 2011, and 22% did afterward.
G-CAN’s next steps are to reach consensus on terminology through online and in-person meetings in 2024, Dr. Jauffret said.
Use of correct gout nomenclature labels improved
In a related presentation, rheumatologist Ellen Prendergast, MBChB, of Dunedin Hospital in New Zealand, reported the results of a newly published review of gout studies before and after G-CAN released consensus recommendations for gout nomenclature in 2019. “There has been improvement in the agreed labels in some areas, but there remains quite significant variability,” she said.
The review examined American College of Rheumatology and EULAR annual meeting abstracts: 596 from 2016-2017 and 392 from 2020-2021. Dr. Prendergast said researchers focused on abstracts instead of published studies in order to gain the most up-to-date understanding of nomenclature.
“Use of the agreed labels ‘urate’ and ‘gout flare’ increased between the two periods. There were 219 of 383 (57.2%) abstracts with the agreed label ‘urate’ in 2016-2017, compared with 164 of 232 (70.7%) in 2020-2021 (P = .001),” the researchers reported. “There were 60 of 175 (34.3%) abstracts with the agreed label ‘gout flare’ in 2016-2017, compared with 57 of 109 (52.3%) in 2020-2021 (P = .003).”
And the use of the term “chronic gout,” which the guidelines recommend against, fell from 29 of 596 (4.9%) abstracts in 2016-2017 to 8 of 392 (2.0%) abstracts in 2020-2021 (P = .02).
One author of the gout nomenclature study reports various consulting fees, speaker fees, or grants outside the submitted work. The other authors of the two studies report no disclosures.
LA JOLLA, CALIF. – Twelve years ago, an international task force of the European Alliance of Associations for Rheumatology (EULAR) released recommendations regarding nomenclature in calcium pyrophosphate deposition disease (CPPD), aiming to standardize the way the condition is described. “Pseudogout” was out, and “acute CPP crystal arthritis” was in, and a confusing array of multi-named phenotypes gained specific labels.
Since 2011, the nomenclature guidelines have been cited hundreds of times, but a new report finds that the medical literature mostly hasn’t followed the recommendations. The findings were released at the annual research symposium of the Gout, Hyperuricemia, and Crystal Associated Disease Network (G-CAN), which is taking another stab at overhauling CPPD nomenclature.
“The objective is to uniform and standardize the labels of the disease, the disease elements, and the clinical states,” rheumatologist Charlotte Jauffret, MD, of the Catholic University of Lille (France), said in a presentation. CPPD is a widely underdiagnosed disease that’s worth the same efforts to standardize nomenclature as occurred in gout, she said.
As Dr. Jauffret explained, CPPD has a diversity of phenotypes in asymptomatic, acute, and chronic forms that pose challenges to diagnosis. “The same terms are used to depict different concepts, and some disease elements are depicted through different names,” she said.
Among other suggestions, the 2011 EULAR recommendations suggested that rheumatologists use the terms chronic CPP crystal inflammatory arthritis instead of “pseudo-rheumatoid arthritis,” osteoarthritis with CPPD, instead of “pseudo-osteoarthritis,” and severe joint degeneration instead of “pseudo-neuropathic joint disease.”
Later reports noted that terms such as CPPD and chondrocalcinosis are still wrongly used interchangeably and called for an international consensus on nomenclature, Dr. Jauffret said.
For the new report, Dr. Jauffret and colleagues examined 985 articles from 2000-2022. The guidelines were often not followed even after the release of the recommendations.
For example, 49% of relevant papers used the label “pseudogout” before 2011, and 43% did afterward. A total of 34% of relevant papers described CPPD as chondrocalcinosis prior to 2011, and 22% did afterward.
G-CAN’s next steps are to reach consensus on terminology through online and in-person meetings in 2024, Dr. Jauffret said.
Use of correct gout nomenclature labels improved
In a related presentation, rheumatologist Ellen Prendergast, MBChB, of Dunedin Hospital in New Zealand, reported the results of a newly published review of gout studies before and after G-CAN released consensus recommendations for gout nomenclature in 2019. “There has been improvement in the agreed labels in some areas, but there remains quite significant variability,” she said.
The review examined American College of Rheumatology and EULAR annual meeting abstracts: 596 from 2016-2017 and 392 from 2020-2021. Dr. Prendergast said researchers focused on abstracts instead of published studies in order to gain the most up-to-date understanding of nomenclature.
“Use of the agreed labels ‘urate’ and ‘gout flare’ increased between the two periods. There were 219 of 383 (57.2%) abstracts with the agreed label ‘urate’ in 2016-2017, compared with 164 of 232 (70.7%) in 2020-2021 (P = .001),” the researchers reported. “There were 60 of 175 (34.3%) abstracts with the agreed label ‘gout flare’ in 2016-2017, compared with 57 of 109 (52.3%) in 2020-2021 (P = .003).”
And the use of the term “chronic gout,” which the guidelines recommend against, fell from 29 of 596 (4.9%) abstracts in 2016-2017 to 8 of 392 (2.0%) abstracts in 2020-2021 (P = .02).
One author of the gout nomenclature study reports various consulting fees, speaker fees, or grants outside the submitted work. The other authors of the two studies report no disclosures.
LA JOLLA, CALIF. – Twelve years ago, an international task force of the European Alliance of Associations for Rheumatology (EULAR) released recommendations regarding nomenclature in calcium pyrophosphate deposition disease (CPPD), aiming to standardize the way the condition is described. “Pseudogout” was out, and “acute CPP crystal arthritis” was in, and a confusing array of multi-named phenotypes gained specific labels.
Since 2011, the nomenclature guidelines have been cited hundreds of times, but a new report finds that the medical literature mostly hasn’t followed the recommendations. The findings were released at the annual research symposium of the Gout, Hyperuricemia, and Crystal Associated Disease Network (G-CAN), which is taking another stab at overhauling CPPD nomenclature.
“The objective is to uniform and standardize the labels of the disease, the disease elements, and the clinical states,” rheumatologist Charlotte Jauffret, MD, of the Catholic University of Lille (France), said in a presentation. CPPD is a widely underdiagnosed disease that’s worth the same efforts to standardize nomenclature as occurred in gout, she said.
As Dr. Jauffret explained, CPPD has a diversity of phenotypes in asymptomatic, acute, and chronic forms that pose challenges to diagnosis. “The same terms are used to depict different concepts, and some disease elements are depicted through different names,” she said.
Among other suggestions, the 2011 EULAR recommendations suggested that rheumatologists use the terms chronic CPP crystal inflammatory arthritis instead of “pseudo-rheumatoid arthritis,” osteoarthritis with CPPD, instead of “pseudo-osteoarthritis,” and severe joint degeneration instead of “pseudo-neuropathic joint disease.”
Later reports noted that terms such as CPPD and chondrocalcinosis are still wrongly used interchangeably and called for an international consensus on nomenclature, Dr. Jauffret said.
For the new report, Dr. Jauffret and colleagues examined 985 articles from 2000-2022. The guidelines were often not followed even after the release of the recommendations.
For example, 49% of relevant papers used the label “pseudogout” before 2011, and 43% did afterward. A total of 34% of relevant papers described CPPD as chondrocalcinosis prior to 2011, and 22% did afterward.
G-CAN’s next steps are to reach consensus on terminology through online and in-person meetings in 2024, Dr. Jauffret said.
Use of correct gout nomenclature labels improved
In a related presentation, rheumatologist Ellen Prendergast, MBChB, of Dunedin Hospital in New Zealand, reported the results of a newly published review of gout studies before and after G-CAN released consensus recommendations for gout nomenclature in 2019. “There has been improvement in the agreed labels in some areas, but there remains quite significant variability,” she said.
The review examined American College of Rheumatology and EULAR annual meeting abstracts: 596 from 2016-2017 and 392 from 2020-2021. Dr. Prendergast said researchers focused on abstracts instead of published studies in order to gain the most up-to-date understanding of nomenclature.
“Use of the agreed labels ‘urate’ and ‘gout flare’ increased between the two periods. There were 219 of 383 (57.2%) abstracts with the agreed label ‘urate’ in 2016-2017, compared with 164 of 232 (70.7%) in 2020-2021 (P = .001),” the researchers reported. “There were 60 of 175 (34.3%) abstracts with the agreed label ‘gout flare’ in 2016-2017, compared with 57 of 109 (52.3%) in 2020-2021 (P = .003).”
And the use of the term “chronic gout,” which the guidelines recommend against, fell from 29 of 596 (4.9%) abstracts in 2016-2017 to 8 of 392 (2.0%) abstracts in 2020-2021 (P = .02).
One author of the gout nomenclature study reports various consulting fees, speaker fees, or grants outside the submitted work. The other authors of the two studies report no disclosures.
At G-CAN 2023
Potential dapagliflozin benefit post MI is not a ‘mandate’
PHILADELPHIA – Giving the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin (Farxiga) to patients with acute myocardial infarction and impaired left ventricular systolic function but no diabetes or chronic heart failure significantly improved a composite of cardiovascular outcomes, a European registry-based randomized trial suggests.
In presenting these results from the DAPA-MI trial, Stefan James, MD, of Uppsala University (Sweden), noted that which the trial described as the hierarchical “win ratio” composite outcomes, compared with patients randomized to placebo plus standard of care.
“The ‘win ratio’ tells us that there’s a 34% higher likelihood of patients having a better cardiometabolic outcome with dapagliflozin vs placebo in terms of the seven components,” James said in an interview. The win ratio was achieved in 32.9% of dapagliflozin patients versus 24.6% of placebo (P < .001).
Dr. James presented the results at the annual scientific sessions of the American Heart Association, and they were published online simultaneously in NEJM Evidence.
Lower-risk patients
DAPA-MI enrolled 4,017 patients from the SWEDEHEART and Myocardial Ischemia National Audit Project registries in Sweden and the United Kingdom, randomly assigning patients to dapagliflozin 10 mg or placebo along with guideline-directed therapy for both groups.
Eligible patients were hemodynamically stable, had an acute MI within 10 days of enrollment, and impaired left ventricular systolic function or a Q-wave MI. Exclusion criteria included history of either type 1 or 2 diabetes, chronic heart failure, poor kidney function, or current treatment with an SGLT2 inhibitor. Baseline demographic characteristics were similar between trial arms.
- The hierarchical seven primary endpoints were:
- Death, with cardiovascular death ranked first followed by noncardiovascular death
- Hospitalization because of heart failure, with adjudicated first followed by investigator-reported HF
- Nonfatal MI
- Atrial fibrillation/flutter event
- New diagnosis of type 2 diabetes
- New York Heart Association functional class at the last visit
- Drop in body weight of at least 5% at the last visit
The key secondary endpoint, Dr. James said, was the primary outcome minus the body weight component, with time to first occurrence of hospitalization for HF or cardiovascular death.
When the seventh factor, body weight decrease, was removed, the differential narrowed: 20.3% versus 16.9% (P = .015). When two or more variables were removed from the composite, the differences were not statistically significant.
For 11 secondary and exploratory outcomes, ranging from CV death or hospitalization for HF to all-cause hospitalization, the outcomes were similar in both the dapagliflozin and placebo groups across the board.
However, the dapagliflozin patients had about half the rate of developing diabetes, compared with the placebo group: 2.1 % versus 3.9%.
The trial initially used the composite of CV death and hospitalization for HF as the primary endpoint, but switched to the seven-item composite endpoint in February because the number of primary composite outcomes was substantially lower than anticipated, Dr. James said.
He acknowledged the study was underpowered for the low-risk population it enrolled. “But if you extended the trial to a larger population and enriched it with a higher-risk population you would probably see an effect,” he said.
“The cardiometabolic benefit was consistent across all prespecified subgroups and there were no new safety concerns,” Dr. James told the attendees. “Clinical event rates were low with no significant difference between randomized groups.”
Not a ringing endorsement
But for invited discussant Stephen D. Wiviott, MD, a cardiologist at Brigham and Women’s Hospital and Harvard Medical School, both in Boston, the DAPA-MI trial result isn’t quite a ringing endorsement of SGLT2 inhibition in these patients.
“From my perspective, DAPA-MI does not suggest a new mandate to expand SGLT2 inhibition to an isolated MI population without other SGLT2 inhibitor indications,” Dr. Wiviott told attendees. “But it does support the safety of its use among patients with acute coronary syndromes.”
However, “these results do not indicate a lack of clinical benefit in patients with prior MI and any of those previously identified conditions – a history of diabetes, coronary heart failure or chronic kidney disease – where SGLT2 inhibition remains a pillar of guideline-directed medical therapy,” Dr. Wiviott said.
In an interview, Dr. Wiviott described the trial design as a “hybrid” in that it used a registry but then added, in his words, “some of the bells and whistles that we have with normal cardiovascular clinical trials.” He further explained: “This is a nice combination of those two things, where they use that as part of the endpoint for the trial but they’re able to add in some of the pieces that you would in a regular registration pathway trial.”
The trial design could serve as a model for future pragmatic therapeutic trials in acute MI, he said, but he acknowledged that DAPA-MI was underpowered to discern many key outcomes.
“They anticipated they were going to have a rate of around 11% of events so they needed to enroll about 6,000 people, but somewhere in the middle of the trial they saw the rate was 2.5%, not 11%, so they had to completely change the trial,” he said of the DAPA-MI investigators.
But an appropriately powered study of SGLT2 inhibition in this population would need about 28,000 patients. “This would be an enormous trial to actually clinically power, so in my sense it’s not going to happen,” Dr. Wiviott said.
The DAPA-MI trial was sponsored by AstraZeneca. Dr. James disclosed relationships with AstraZeneca, Janssen, and Amgen. Dr. Wiviott disclosed relationships with Amgen, AstraZeneca, Janssen, Merck, Pfizer, Icon Clinical, Novo Nordisk, and Varian.
PHILADELPHIA – Giving the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin (Farxiga) to patients with acute myocardial infarction and impaired left ventricular systolic function but no diabetes or chronic heart failure significantly improved a composite of cardiovascular outcomes, a European registry-based randomized trial suggests.
In presenting these results from the DAPA-MI trial, Stefan James, MD, of Uppsala University (Sweden), noted that which the trial described as the hierarchical “win ratio” composite outcomes, compared with patients randomized to placebo plus standard of care.
“The ‘win ratio’ tells us that there’s a 34% higher likelihood of patients having a better cardiometabolic outcome with dapagliflozin vs placebo in terms of the seven components,” James said in an interview. The win ratio was achieved in 32.9% of dapagliflozin patients versus 24.6% of placebo (P < .001).
Dr. James presented the results at the annual scientific sessions of the American Heart Association, and they were published online simultaneously in NEJM Evidence.
Lower-risk patients
DAPA-MI enrolled 4,017 patients from the SWEDEHEART and Myocardial Ischemia National Audit Project registries in Sweden and the United Kingdom, randomly assigning patients to dapagliflozin 10 mg or placebo along with guideline-directed therapy for both groups.
Eligible patients were hemodynamically stable, had an acute MI within 10 days of enrollment, and impaired left ventricular systolic function or a Q-wave MI. Exclusion criteria included history of either type 1 or 2 diabetes, chronic heart failure, poor kidney function, or current treatment with an SGLT2 inhibitor. Baseline demographic characteristics were similar between trial arms.
- The hierarchical seven primary endpoints were:
- Death, with cardiovascular death ranked first followed by noncardiovascular death
- Hospitalization because of heart failure, with adjudicated first followed by investigator-reported HF
- Nonfatal MI
- Atrial fibrillation/flutter event
- New diagnosis of type 2 diabetes
- New York Heart Association functional class at the last visit
- Drop in body weight of at least 5% at the last visit
The key secondary endpoint, Dr. James said, was the primary outcome minus the body weight component, with time to first occurrence of hospitalization for HF or cardiovascular death.
When the seventh factor, body weight decrease, was removed, the differential narrowed: 20.3% versus 16.9% (P = .015). When two or more variables were removed from the composite, the differences were not statistically significant.
For 11 secondary and exploratory outcomes, ranging from CV death or hospitalization for HF to all-cause hospitalization, the outcomes were similar in both the dapagliflozin and placebo groups across the board.
However, the dapagliflozin patients had about half the rate of developing diabetes, compared with the placebo group: 2.1 % versus 3.9%.
The trial initially used the composite of CV death and hospitalization for HF as the primary endpoint, but switched to the seven-item composite endpoint in February because the number of primary composite outcomes was substantially lower than anticipated, Dr. James said.
He acknowledged the study was underpowered for the low-risk population it enrolled. “But if you extended the trial to a larger population and enriched it with a higher-risk population you would probably see an effect,” he said.
“The cardiometabolic benefit was consistent across all prespecified subgroups and there were no new safety concerns,” Dr. James told the attendees. “Clinical event rates were low with no significant difference between randomized groups.”
Not a ringing endorsement
But for invited discussant Stephen D. Wiviott, MD, a cardiologist at Brigham and Women’s Hospital and Harvard Medical School, both in Boston, the DAPA-MI trial result isn’t quite a ringing endorsement of SGLT2 inhibition in these patients.
“From my perspective, DAPA-MI does not suggest a new mandate to expand SGLT2 inhibition to an isolated MI population without other SGLT2 inhibitor indications,” Dr. Wiviott told attendees. “But it does support the safety of its use among patients with acute coronary syndromes.”
However, “these results do not indicate a lack of clinical benefit in patients with prior MI and any of those previously identified conditions – a history of diabetes, coronary heart failure or chronic kidney disease – where SGLT2 inhibition remains a pillar of guideline-directed medical therapy,” Dr. Wiviott said.
In an interview, Dr. Wiviott described the trial design as a “hybrid” in that it used a registry but then added, in his words, “some of the bells and whistles that we have with normal cardiovascular clinical trials.” He further explained: “This is a nice combination of those two things, where they use that as part of the endpoint for the trial but they’re able to add in some of the pieces that you would in a regular registration pathway trial.”
The trial design could serve as a model for future pragmatic therapeutic trials in acute MI, he said, but he acknowledged that DAPA-MI was underpowered to discern many key outcomes.
“They anticipated they were going to have a rate of around 11% of events so they needed to enroll about 6,000 people, but somewhere in the middle of the trial they saw the rate was 2.5%, not 11%, so they had to completely change the trial,” he said of the DAPA-MI investigators.
But an appropriately powered study of SGLT2 inhibition in this population would need about 28,000 patients. “This would be an enormous trial to actually clinically power, so in my sense it’s not going to happen,” Dr. Wiviott said.
The DAPA-MI trial was sponsored by AstraZeneca. Dr. James disclosed relationships with AstraZeneca, Janssen, and Amgen. Dr. Wiviott disclosed relationships with Amgen, AstraZeneca, Janssen, Merck, Pfizer, Icon Clinical, Novo Nordisk, and Varian.
PHILADELPHIA – Giving the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin (Farxiga) to patients with acute myocardial infarction and impaired left ventricular systolic function but no diabetes or chronic heart failure significantly improved a composite of cardiovascular outcomes, a European registry-based randomized trial suggests.
In presenting these results from the DAPA-MI trial, Stefan James, MD, of Uppsala University (Sweden), noted that which the trial described as the hierarchical “win ratio” composite outcomes, compared with patients randomized to placebo plus standard of care.
“The ‘win ratio’ tells us that there’s a 34% higher likelihood of patients having a better cardiometabolic outcome with dapagliflozin vs placebo in terms of the seven components,” James said in an interview. The win ratio was achieved in 32.9% of dapagliflozin patients versus 24.6% of placebo (P < .001).
Dr. James presented the results at the annual scientific sessions of the American Heart Association, and they were published online simultaneously in NEJM Evidence.
Lower-risk patients
DAPA-MI enrolled 4,017 patients from the SWEDEHEART and Myocardial Ischemia National Audit Project registries in Sweden and the United Kingdom, randomly assigning patients to dapagliflozin 10 mg or placebo along with guideline-directed therapy for both groups.
Eligible patients were hemodynamically stable, had an acute MI within 10 days of enrollment, and impaired left ventricular systolic function or a Q-wave MI. Exclusion criteria included history of either type 1 or 2 diabetes, chronic heart failure, poor kidney function, or current treatment with an SGLT2 inhibitor. Baseline demographic characteristics were similar between trial arms.
- The hierarchical seven primary endpoints were:
- Death, with cardiovascular death ranked first followed by noncardiovascular death
- Hospitalization because of heart failure, with adjudicated first followed by investigator-reported HF
- Nonfatal MI
- Atrial fibrillation/flutter event
- New diagnosis of type 2 diabetes
- New York Heart Association functional class at the last visit
- Drop in body weight of at least 5% at the last visit
The key secondary endpoint, Dr. James said, was the primary outcome minus the body weight component, with time to first occurrence of hospitalization for HF or cardiovascular death.
When the seventh factor, body weight decrease, was removed, the differential narrowed: 20.3% versus 16.9% (P = .015). When two or more variables were removed from the composite, the differences were not statistically significant.
For 11 secondary and exploratory outcomes, ranging from CV death or hospitalization for HF to all-cause hospitalization, the outcomes were similar in both the dapagliflozin and placebo groups across the board.
However, the dapagliflozin patients had about half the rate of developing diabetes, compared with the placebo group: 2.1 % versus 3.9%.
The trial initially used the composite of CV death and hospitalization for HF as the primary endpoint, but switched to the seven-item composite endpoint in February because the number of primary composite outcomes was substantially lower than anticipated, Dr. James said.
He acknowledged the study was underpowered for the low-risk population it enrolled. “But if you extended the trial to a larger population and enriched it with a higher-risk population you would probably see an effect,” he said.
“The cardiometabolic benefit was consistent across all prespecified subgroups and there were no new safety concerns,” Dr. James told the attendees. “Clinical event rates were low with no significant difference between randomized groups.”
Not a ringing endorsement
But for invited discussant Stephen D. Wiviott, MD, a cardiologist at Brigham and Women’s Hospital and Harvard Medical School, both in Boston, the DAPA-MI trial result isn’t quite a ringing endorsement of SGLT2 inhibition in these patients.
“From my perspective, DAPA-MI does not suggest a new mandate to expand SGLT2 inhibition to an isolated MI population without other SGLT2 inhibitor indications,” Dr. Wiviott told attendees. “But it does support the safety of its use among patients with acute coronary syndromes.”
However, “these results do not indicate a lack of clinical benefit in patients with prior MI and any of those previously identified conditions – a history of diabetes, coronary heart failure or chronic kidney disease – where SGLT2 inhibition remains a pillar of guideline-directed medical therapy,” Dr. Wiviott said.
In an interview, Dr. Wiviott described the trial design as a “hybrid” in that it used a registry but then added, in his words, “some of the bells and whistles that we have with normal cardiovascular clinical trials.” He further explained: “This is a nice combination of those two things, where they use that as part of the endpoint for the trial but they’re able to add in some of the pieces that you would in a regular registration pathway trial.”
The trial design could serve as a model for future pragmatic therapeutic trials in acute MI, he said, but he acknowledged that DAPA-MI was underpowered to discern many key outcomes.
“They anticipated they were going to have a rate of around 11% of events so they needed to enroll about 6,000 people, but somewhere in the middle of the trial they saw the rate was 2.5%, not 11%, so they had to completely change the trial,” he said of the DAPA-MI investigators.
But an appropriately powered study of SGLT2 inhibition in this population would need about 28,000 patients. “This would be an enormous trial to actually clinically power, so in my sense it’s not going to happen,” Dr. Wiviott said.
The DAPA-MI trial was sponsored by AstraZeneca. Dr. James disclosed relationships with AstraZeneca, Janssen, and Amgen. Dr. Wiviott disclosed relationships with Amgen, AstraZeneca, Janssen, Merck, Pfizer, Icon Clinical, Novo Nordisk, and Varian.
AT AHA 2023
Semaglutide ‘a new pathway’ to CVD risk reduction: SELECT
over the approximately 3-year follow-up in patients with overweight or obesity and cardiovascular disease but not diabetes.
“This is a very exciting set of results. I think it is going to have a big impact on a large number of people,” lead investigator A. Michael Lincoff, MD, vice chair for research in the department of cardiovascular medicine at the Cleveland Clinic, said in an interview.
“And from a scientific standpoint, these data show that we now have a new pathway or a new modifiable risk factor for cardiovascular disease that we can use in our patients who have overweight or obesity,” he added.
The trial involved 17,604 patients with a history of cardiovascular disease and a body mass index of 27 kg/m2 or above (mean BMI was 33), who were randomly assigned to the glucagonlike peptide–1 (GLP-1) agonist semaglutide, given by subcutaneous injection once weekly at a gradually escalating dose up to 2.4 mg daily by week 16, or placebo. The mean baseline glycated hemoglobin level was 5.8% and 66.4% of patients met the criteria for prediabetes.
Patients lost a mean of 9.4% of body weight over the first 2 years with semaglutide versus 0.88% with placebo.
The primary cardiovascular endpoint – a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke – was reduced significantly, with a hazard ratio of 0.80 (95% confidence interval, 0.72-0.90; P < .001).
Death from cardiovascular causes, the first confirmatory secondary endpoint, showed a 15% reduction (HR, 0.85; P = .07) but this missed meeting criteria for statistical significance, and because of the hierarchical design of the trial, this meant that superiority testing was not performed for the remaining confirmatory secondary endpoints.
However, results showed reductions of around 20% for the heart failure composite endpoint and for all-cause mortality, with confidence intervals that did not cross 1.0, and directionally consistent effects were observed for all supportive secondary endpoints.
The HR for the heart failure composite endpoint was 0.82 (95% CI, 0.71-0.96), and the HR for death from any cause was 0.81 (95% CI, 0.71-0.93). Nonfatal MI was reduced by 28% (HR 0.72; 95% CI, 0.61-0.85).
The effects of semaglutide on the primary endpoint appeared to be similar across all prespecified subgroups.
Adverse events leading to discontinuation of treatment occurred in 16.6% in the semaglutide group, mostly gastrointestinal effects, and in 8.2% in the placebo group.
The trial results were presented by Dr. Lincoff at the annual scientific sessions of the American Heart Association . They were also simultaneously published online in the New England Journal of Medicine.
Dr. Lincoff explained that there is a growing pandemic of overweight and obesity worldwide with clear evidence for years that these conditions increase the risk of cardiovascular events – and yet there has been no evidence, until now, that any pharmacologic or lifestyle therapy can reduce the increased risk conferred by overweight/obesity.
“Patients in the trial were already taking standard of care therapies for other risk factors, such as hypertension and cholesterol, so this drug is giving additional benefit,” he said.
Dr. Lincoff believes these data will lead to a large increase in use of semaglutide, which is already available for the treatment of obesity and diabetes but can be difficult to get reimbursed.
“There is a lot of difficulty getting payors to pay for this drug for weight management. But with this new data from the SELECT trial there should be more willingness – at least in the population with a history of cardiovascular disease,” he commented. In diabetes, where it is already established that there is a cardiovascular risk reduction, it is easier to get these drugs reimbursed, he noted.
On the outcome data, Dr. Lincoff said he could not explain why cardiovascular death was not significantly reduced while all-cause mortality appeared to be cut more definitively.
“The cardiovascular death curves separated, then merged, then separated again. We don’t really know what is going on there. It may be that some deaths were misclassified. This trial was conducted through the COVID era and there may have been less information available on some patients because of that.”
But he added: “The all-cause mortality is more reassuring, as it doesn’t depend on classifying cause of death. Because of the design of the trial, we can’t formally claim a reduction in all-cause mortality, but the results do suggest there is an effect on this endpoint. And all the different types of cardiovascular events were similarly reduced in a consistent way, with similar effects seen across all subgroups. That is very reassuring.”
‘A new era’ for patients with obesity
Outside experts in the field were also impressed with the data.
Designated discussant of the trial at the AHA meeting, Ania Jastreboff, MD, associate professor medicine (endocrinology) at Yale University, New Haven, Conn., said the SELECT trial was “a turning point in the treatment of obesity and a call to action.
“Now is the time to treat obesity to improve health outcomes in people with cardiovascular disease,” she said.
Dr. Jastreboff noted that high BMI was estimated to have accounted for 4 million deaths worldwide in 2015, two-thirds of which were caused by cardiovascular disease. And she presented data showing that U.S. individuals meeting the SELECT criteria increased from 4.3 million in 2011-12 to 6.6 million in 2017-18.
She highlighted one major limitation of the SELECT trial: it enrolled a low number of women (38%) and ethnic minorities, with only 12% of the trial population being Black.
Deepak L. Bhatt, MD, director of Mount Sinai Fuster Heart Hospital, New York, described the SELECT results as “altogether a compelling package of data.”
“These results are even better than I had expected,” Dr. Bhatt said in an interview. “There is a significant reduction in MI as I had anticipated, but additionally, there is a reduction in all-cause death. One can debate the statistics, though on a common-sense level, I think it is a real finding,” he noted.
“Given that MI, heart failure, nephropathy, and revascularization are all reduced, and even stroke is numerically lower, it makes sense that all-cause mortality would be reduced,” he said. “To me, apart from the GI side effects, this counts as a home run.”
Steve Nissen, MD, chief academic officer at the Cleveland Clinic’s Heart, Vascular and Thoracic Institute, was similarly upbeat.
“These data prove what many of us have long suspected – that losing weight can reduce cardiovascular morbidity and mortality. This is great news for patients living with obesity. The obesity epidemic is out of control,” he added. “We need to have therapies that improve cardiovascular outcomes caused by obesity and this shows that semaglutide can do that. I think this is the beginning of a whole new era for patients with obesity.”
Michelle O’Donoghue, MD, associate professor of medicine at Harvard Medical School, Boston, called the results of SELECT “both intriguing and compelling. Certainly, these findings lend further support to the use of semaglutide in a much broader secondary prevention population of individuals with obesity.”
Christie Ballantyne, MD, director of the center for cardiometabolic disease prevention at Baylor College of Medicine, Houston, described the SELECT study as “a landmark trial which will change the practice of medicine in regard to how we treat obesity.”
He compared it with the landmark 4S trial in 1994, the first study in the area of cholesterol lowering therapy to show a clear benefit in reducing cardiovascular events and total mortality, and “began a drastic change in the way that physicians approached treatment of cholesterol.”
On the more robust reduction in all-cause death, compared with cardiovascular death,
Dr. Ballantyne pointed out: “Adjudication of dead or alive is something that everyone gets right. In contrast, the cause of death is sometime difficult to ascertain. Most importantly, the benefit on total mortality also provides assurance that this therapy does not have some adverse effect on increasing noncardiovascular deaths.”
Gastrointestinal adverse effects
On the side effects seen with semaglutide, Dr. Lincoff reported that 10% of patients in the semaglutide group discontinued treatment because of GI side effects versus 2% in the placebo arm. He said this was “an expected issue.”
“GI effects, such as nausea, vomiting and diarrhea, are known side effects of this whole class of drugs. The dose is slowly escalated to manage these adverse effects but there will be a proportion of patients who can’t tolerate it, although the vast majority are able to continue.”
He noted that, while dose reduction was allowed, of the patients who were still on the drug at 2 years, 77% were on the full dose, and 23% were on a reduced dose.
Dr. Lincoff pointed out that there were no serious adverse events with semaglutide. “This is the largest database by far now on the drug with a long-term follow up and we didn’t see the emergence of any new safety signals, which is very reassuring.”
Dr. Nissen said the 16% rate of patients stopping the drug because of tolerability “is not a trivial number.”
He noted that the semaglutide dose used in this study was larger than that used in diabetes.
“They did this to try to achieve more weight loss but then you get more issues with tolerability. It’s a trade-off. If patients are experiencing adverse effects, the dose can be reduced, but then you will lose some effect. All the GLP-1 agonists have GI side effects – it’s part of the way that they work.”
Just weight loss or other actions too?
Speculating on the mechanism behind the reduction in cardiovascular events with semaglutide, Dr. Lincoff does not think it is just weight reduction.
“The event curves start to diverge very soon after the start of the trial and yet the maximum weight loss doesn’t occur until about 65 weeks. I think something else is going on.”
In the paper, the researchers noted that GLP-1 agonists have been shown in animal studies to reduce inflammation, improve endothelial and left ventricular function, promote plaque stability, and decrease platelet aggregation. In this trial, semaglutide was associated with changes in multiple biomarkers of cardiovascular risk, including blood pressure, waist circumference, glycemic control, nephropathy, and levels of lipids and C-reactive protein.
Dr. Lincoff also pointed out that similar benefits were seen in patients with different levels of overweight, and in those who were prediabetic and those who weren’t, so benefit was not dependent on baseline BMI or glycated hemoglobin levels.
Dr. O’Donoghue agreed that other effects, as well as weight loss, could be involved. “The reduction in events with semaglutide appeared very early after initiation and far preceded the drug’s maximal effects on weight reduction. This might suggest that the drug offers other cardioprotective effects through pathways independent of weight loss. Certainly, semaglutide and the other GLP-1 agonists appear to attenuate inflammation, and the patterns of redistribution of adipose tissue may also be of interest.”
She also pointed out that the reduction in cardiovascular events appeared even earlier in this population of obese nondiabetic patients with cardiovascular disease than in prior studies of patients with diabetes. “It may suggest that there is particular benefit for this type of therapy in patients with an inflammatory milieu. I look forward to seeing further analyses to help tease apart the correlation between changes in inflammation, observed weight loss and cardiovascular benefit.”
Effect on clinical practice
With the majority of patients with cardiovascular disease being overweight, these results are obviously going to increase demand for semaglutide, but cost and availability are going to be an issue.
Dr. Bhatt noted that semaglutide is already very popular. “Weight loss drugs are somewhat different from other medications. I can spend 30 minutes trying to convince a patient to take a statin, but here people realize it’s going to cause weight loss and they come in asking for it even if they don’t strictly need it. I think it’s good to have cardiovascular outcome data because now at least for this population of patients, we have evidence to prescribe it.”
He agreed with Dr. Lincoff that these new data should encourage insurance companies to cover the drug, because in reducing cardiovascular events it should also improve downstream health care costs.
“It is providing clear cardiovascular and kidney benefit, so it is in the best interest to the health care system to fund this drug,” he said. “I hope insurers look at it rationally in this way, but they may also be frightened of the explosion of patients wanting this drug and now doctors wanting to prescribe it and how that would affect their shorter-term costs.”
Dr. Lincoff said it would not be easy to prioritize certain groups. “We couldn’t identify any subgroup who showed particularly more benefit than any others. But in the evolution of any therapy, there is a time period where it is in short supply and prohibitively expensive, then over time when there is some competition and pricing deals occur as more people are advocating for it, they become more available.”
‘A welcome treatment option’
In an editorial accompanying publication of the trial, Amit Khera, MD, University of Texas Southwestern Medical Center, Dallas, and Tiffany Powell-Wiley, MD, MPH, National Institutes of Health, Bethesda, noted that baseline risk factors such as LDL cholesterol (78 mg/dL) and systolic blood pressure (131 mm Hg) were not ideal in the semaglutide group in this trial, and they suggest that the benefits of semaglutide may be attenuated when these measures are better controlled.
But given that more than 20 million people in the United States have coronary artery disease, with the majority having overweight or obesity and only approximately 30% having concomitant diabetes, they said that, even in the context of well-controlled risk factors and very low LDL cholesterol levels, the residual risk of atherosclerotic cardiovascular disease in these persons is unacceptably high. “Thus, the SELECT trial provides a welcome treatment option that can be extended to millions of additional patients.”
However, the editorialists cautioned that semaglutide at current pricing comes with a significant cost to both patients and society, which makes this treatment inaccessible for many.
They added that intensive lifestyle interventions and bariatric surgery remain effective but underutilized options for obesity, and that the prevention of obesity before it develops should be the primary goal.
The SELECT trial was supported by Novo Nordisk, and several coauthors are employees of the company. Dr. Lincoff is a consultant for Novo Nordisk. Dr. Bhatt and Dr. Nissen are involved in a cardiovascular outcomes trial with a new investigational weight loss drug from Lilly. Dr. Bhatt and Dr. Ballantyne are also investigators in a Novo Nordisk trial of a new anti-inflammatory drug.
over the approximately 3-year follow-up in patients with overweight or obesity and cardiovascular disease but not diabetes.
“This is a very exciting set of results. I think it is going to have a big impact on a large number of people,” lead investigator A. Michael Lincoff, MD, vice chair for research in the department of cardiovascular medicine at the Cleveland Clinic, said in an interview.
“And from a scientific standpoint, these data show that we now have a new pathway or a new modifiable risk factor for cardiovascular disease that we can use in our patients who have overweight or obesity,” he added.
The trial involved 17,604 patients with a history of cardiovascular disease and a body mass index of 27 kg/m2 or above (mean BMI was 33), who were randomly assigned to the glucagonlike peptide–1 (GLP-1) agonist semaglutide, given by subcutaneous injection once weekly at a gradually escalating dose up to 2.4 mg daily by week 16, or placebo. The mean baseline glycated hemoglobin level was 5.8% and 66.4% of patients met the criteria for prediabetes.
Patients lost a mean of 9.4% of body weight over the first 2 years with semaglutide versus 0.88% with placebo.
The primary cardiovascular endpoint – a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke – was reduced significantly, with a hazard ratio of 0.80 (95% confidence interval, 0.72-0.90; P < .001).
Death from cardiovascular causes, the first confirmatory secondary endpoint, showed a 15% reduction (HR, 0.85; P = .07) but this missed meeting criteria for statistical significance, and because of the hierarchical design of the trial, this meant that superiority testing was not performed for the remaining confirmatory secondary endpoints.
However, results showed reductions of around 20% for the heart failure composite endpoint and for all-cause mortality, with confidence intervals that did not cross 1.0, and directionally consistent effects were observed for all supportive secondary endpoints.
The HR for the heart failure composite endpoint was 0.82 (95% CI, 0.71-0.96), and the HR for death from any cause was 0.81 (95% CI, 0.71-0.93). Nonfatal MI was reduced by 28% (HR 0.72; 95% CI, 0.61-0.85).
The effects of semaglutide on the primary endpoint appeared to be similar across all prespecified subgroups.
Adverse events leading to discontinuation of treatment occurred in 16.6% in the semaglutide group, mostly gastrointestinal effects, and in 8.2% in the placebo group.
The trial results were presented by Dr. Lincoff at the annual scientific sessions of the American Heart Association . They were also simultaneously published online in the New England Journal of Medicine.
Dr. Lincoff explained that there is a growing pandemic of overweight and obesity worldwide with clear evidence for years that these conditions increase the risk of cardiovascular events – and yet there has been no evidence, until now, that any pharmacologic or lifestyle therapy can reduce the increased risk conferred by overweight/obesity.
“Patients in the trial were already taking standard of care therapies for other risk factors, such as hypertension and cholesterol, so this drug is giving additional benefit,” he said.
Dr. Lincoff believes these data will lead to a large increase in use of semaglutide, which is already available for the treatment of obesity and diabetes but can be difficult to get reimbursed.
“There is a lot of difficulty getting payors to pay for this drug for weight management. But with this new data from the SELECT trial there should be more willingness – at least in the population with a history of cardiovascular disease,” he commented. In diabetes, where it is already established that there is a cardiovascular risk reduction, it is easier to get these drugs reimbursed, he noted.
On the outcome data, Dr. Lincoff said he could not explain why cardiovascular death was not significantly reduced while all-cause mortality appeared to be cut more definitively.
“The cardiovascular death curves separated, then merged, then separated again. We don’t really know what is going on there. It may be that some deaths were misclassified. This trial was conducted through the COVID era and there may have been less information available on some patients because of that.”
But he added: “The all-cause mortality is more reassuring, as it doesn’t depend on classifying cause of death. Because of the design of the trial, we can’t formally claim a reduction in all-cause mortality, but the results do suggest there is an effect on this endpoint. And all the different types of cardiovascular events were similarly reduced in a consistent way, with similar effects seen across all subgroups. That is very reassuring.”
‘A new era’ for patients with obesity
Outside experts in the field were also impressed with the data.
Designated discussant of the trial at the AHA meeting, Ania Jastreboff, MD, associate professor medicine (endocrinology) at Yale University, New Haven, Conn., said the SELECT trial was “a turning point in the treatment of obesity and a call to action.
“Now is the time to treat obesity to improve health outcomes in people with cardiovascular disease,” she said.
Dr. Jastreboff noted that high BMI was estimated to have accounted for 4 million deaths worldwide in 2015, two-thirds of which were caused by cardiovascular disease. And she presented data showing that U.S. individuals meeting the SELECT criteria increased from 4.3 million in 2011-12 to 6.6 million in 2017-18.
She highlighted one major limitation of the SELECT trial: it enrolled a low number of women (38%) and ethnic minorities, with only 12% of the trial population being Black.
Deepak L. Bhatt, MD, director of Mount Sinai Fuster Heart Hospital, New York, described the SELECT results as “altogether a compelling package of data.”
“These results are even better than I had expected,” Dr. Bhatt said in an interview. “There is a significant reduction in MI as I had anticipated, but additionally, there is a reduction in all-cause death. One can debate the statistics, though on a common-sense level, I think it is a real finding,” he noted.
“Given that MI, heart failure, nephropathy, and revascularization are all reduced, and even stroke is numerically lower, it makes sense that all-cause mortality would be reduced,” he said. “To me, apart from the GI side effects, this counts as a home run.”
Steve Nissen, MD, chief academic officer at the Cleveland Clinic’s Heart, Vascular and Thoracic Institute, was similarly upbeat.
“These data prove what many of us have long suspected – that losing weight can reduce cardiovascular morbidity and mortality. This is great news for patients living with obesity. The obesity epidemic is out of control,” he added. “We need to have therapies that improve cardiovascular outcomes caused by obesity and this shows that semaglutide can do that. I think this is the beginning of a whole new era for patients with obesity.”
Michelle O’Donoghue, MD, associate professor of medicine at Harvard Medical School, Boston, called the results of SELECT “both intriguing and compelling. Certainly, these findings lend further support to the use of semaglutide in a much broader secondary prevention population of individuals with obesity.”
Christie Ballantyne, MD, director of the center for cardiometabolic disease prevention at Baylor College of Medicine, Houston, described the SELECT study as “a landmark trial which will change the practice of medicine in regard to how we treat obesity.”
He compared it with the landmark 4S trial in 1994, the first study in the area of cholesterol lowering therapy to show a clear benefit in reducing cardiovascular events and total mortality, and “began a drastic change in the way that physicians approached treatment of cholesterol.”
On the more robust reduction in all-cause death, compared with cardiovascular death,
Dr. Ballantyne pointed out: “Adjudication of dead or alive is something that everyone gets right. In contrast, the cause of death is sometime difficult to ascertain. Most importantly, the benefit on total mortality also provides assurance that this therapy does not have some adverse effect on increasing noncardiovascular deaths.”
Gastrointestinal adverse effects
On the side effects seen with semaglutide, Dr. Lincoff reported that 10% of patients in the semaglutide group discontinued treatment because of GI side effects versus 2% in the placebo arm. He said this was “an expected issue.”
“GI effects, such as nausea, vomiting and diarrhea, are known side effects of this whole class of drugs. The dose is slowly escalated to manage these adverse effects but there will be a proportion of patients who can’t tolerate it, although the vast majority are able to continue.”
He noted that, while dose reduction was allowed, of the patients who were still on the drug at 2 years, 77% were on the full dose, and 23% were on a reduced dose.
Dr. Lincoff pointed out that there were no serious adverse events with semaglutide. “This is the largest database by far now on the drug with a long-term follow up and we didn’t see the emergence of any new safety signals, which is very reassuring.”
Dr. Nissen said the 16% rate of patients stopping the drug because of tolerability “is not a trivial number.”
He noted that the semaglutide dose used in this study was larger than that used in diabetes.
“They did this to try to achieve more weight loss but then you get more issues with tolerability. It’s a trade-off. If patients are experiencing adverse effects, the dose can be reduced, but then you will lose some effect. All the GLP-1 agonists have GI side effects – it’s part of the way that they work.”
Just weight loss or other actions too?
Speculating on the mechanism behind the reduction in cardiovascular events with semaglutide, Dr. Lincoff does not think it is just weight reduction.
“The event curves start to diverge very soon after the start of the trial and yet the maximum weight loss doesn’t occur until about 65 weeks. I think something else is going on.”
In the paper, the researchers noted that GLP-1 agonists have been shown in animal studies to reduce inflammation, improve endothelial and left ventricular function, promote plaque stability, and decrease platelet aggregation. In this trial, semaglutide was associated with changes in multiple biomarkers of cardiovascular risk, including blood pressure, waist circumference, glycemic control, nephropathy, and levels of lipids and C-reactive protein.
Dr. Lincoff also pointed out that similar benefits were seen in patients with different levels of overweight, and in those who were prediabetic and those who weren’t, so benefit was not dependent on baseline BMI or glycated hemoglobin levels.
Dr. O’Donoghue agreed that other effects, as well as weight loss, could be involved. “The reduction in events with semaglutide appeared very early after initiation and far preceded the drug’s maximal effects on weight reduction. This might suggest that the drug offers other cardioprotective effects through pathways independent of weight loss. Certainly, semaglutide and the other GLP-1 agonists appear to attenuate inflammation, and the patterns of redistribution of adipose tissue may also be of interest.”
She also pointed out that the reduction in cardiovascular events appeared even earlier in this population of obese nondiabetic patients with cardiovascular disease than in prior studies of patients with diabetes. “It may suggest that there is particular benefit for this type of therapy in patients with an inflammatory milieu. I look forward to seeing further analyses to help tease apart the correlation between changes in inflammation, observed weight loss and cardiovascular benefit.”
Effect on clinical practice
With the majority of patients with cardiovascular disease being overweight, these results are obviously going to increase demand for semaglutide, but cost and availability are going to be an issue.
Dr. Bhatt noted that semaglutide is already very popular. “Weight loss drugs are somewhat different from other medications. I can spend 30 minutes trying to convince a patient to take a statin, but here people realize it’s going to cause weight loss and they come in asking for it even if they don’t strictly need it. I think it’s good to have cardiovascular outcome data because now at least for this population of patients, we have evidence to prescribe it.”
He agreed with Dr. Lincoff that these new data should encourage insurance companies to cover the drug, because in reducing cardiovascular events it should also improve downstream health care costs.
“It is providing clear cardiovascular and kidney benefit, so it is in the best interest to the health care system to fund this drug,” he said. “I hope insurers look at it rationally in this way, but they may also be frightened of the explosion of patients wanting this drug and now doctors wanting to prescribe it and how that would affect their shorter-term costs.”
Dr. Lincoff said it would not be easy to prioritize certain groups. “We couldn’t identify any subgroup who showed particularly more benefit than any others. But in the evolution of any therapy, there is a time period where it is in short supply and prohibitively expensive, then over time when there is some competition and pricing deals occur as more people are advocating for it, they become more available.”
‘A welcome treatment option’
In an editorial accompanying publication of the trial, Amit Khera, MD, University of Texas Southwestern Medical Center, Dallas, and Tiffany Powell-Wiley, MD, MPH, National Institutes of Health, Bethesda, noted that baseline risk factors such as LDL cholesterol (78 mg/dL) and systolic blood pressure (131 mm Hg) were not ideal in the semaglutide group in this trial, and they suggest that the benefits of semaglutide may be attenuated when these measures are better controlled.
But given that more than 20 million people in the United States have coronary artery disease, with the majority having overweight or obesity and only approximately 30% having concomitant diabetes, they said that, even in the context of well-controlled risk factors and very low LDL cholesterol levels, the residual risk of atherosclerotic cardiovascular disease in these persons is unacceptably high. “Thus, the SELECT trial provides a welcome treatment option that can be extended to millions of additional patients.”
However, the editorialists cautioned that semaglutide at current pricing comes with a significant cost to both patients and society, which makes this treatment inaccessible for many.
They added that intensive lifestyle interventions and bariatric surgery remain effective but underutilized options for obesity, and that the prevention of obesity before it develops should be the primary goal.
The SELECT trial was supported by Novo Nordisk, and several coauthors are employees of the company. Dr. Lincoff is a consultant for Novo Nordisk. Dr. Bhatt and Dr. Nissen are involved in a cardiovascular outcomes trial with a new investigational weight loss drug from Lilly. Dr. Bhatt and Dr. Ballantyne are also investigators in a Novo Nordisk trial of a new anti-inflammatory drug.
over the approximately 3-year follow-up in patients with overweight or obesity and cardiovascular disease but not diabetes.
“This is a very exciting set of results. I think it is going to have a big impact on a large number of people,” lead investigator A. Michael Lincoff, MD, vice chair for research in the department of cardiovascular medicine at the Cleveland Clinic, said in an interview.
“And from a scientific standpoint, these data show that we now have a new pathway or a new modifiable risk factor for cardiovascular disease that we can use in our patients who have overweight or obesity,” he added.
The trial involved 17,604 patients with a history of cardiovascular disease and a body mass index of 27 kg/m2 or above (mean BMI was 33), who were randomly assigned to the glucagonlike peptide–1 (GLP-1) agonist semaglutide, given by subcutaneous injection once weekly at a gradually escalating dose up to 2.4 mg daily by week 16, or placebo. The mean baseline glycated hemoglobin level was 5.8% and 66.4% of patients met the criteria for prediabetes.
Patients lost a mean of 9.4% of body weight over the first 2 years with semaglutide versus 0.88% with placebo.
The primary cardiovascular endpoint – a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke – was reduced significantly, with a hazard ratio of 0.80 (95% confidence interval, 0.72-0.90; P < .001).
Death from cardiovascular causes, the first confirmatory secondary endpoint, showed a 15% reduction (HR, 0.85; P = .07) but this missed meeting criteria for statistical significance, and because of the hierarchical design of the trial, this meant that superiority testing was not performed for the remaining confirmatory secondary endpoints.
However, results showed reductions of around 20% for the heart failure composite endpoint and for all-cause mortality, with confidence intervals that did not cross 1.0, and directionally consistent effects were observed for all supportive secondary endpoints.
The HR for the heart failure composite endpoint was 0.82 (95% CI, 0.71-0.96), and the HR for death from any cause was 0.81 (95% CI, 0.71-0.93). Nonfatal MI was reduced by 28% (HR 0.72; 95% CI, 0.61-0.85).
The effects of semaglutide on the primary endpoint appeared to be similar across all prespecified subgroups.
Adverse events leading to discontinuation of treatment occurred in 16.6% in the semaglutide group, mostly gastrointestinal effects, and in 8.2% in the placebo group.
The trial results were presented by Dr. Lincoff at the annual scientific sessions of the American Heart Association . They were also simultaneously published online in the New England Journal of Medicine.
Dr. Lincoff explained that there is a growing pandemic of overweight and obesity worldwide with clear evidence for years that these conditions increase the risk of cardiovascular events – and yet there has been no evidence, until now, that any pharmacologic or lifestyle therapy can reduce the increased risk conferred by overweight/obesity.
“Patients in the trial were already taking standard of care therapies for other risk factors, such as hypertension and cholesterol, so this drug is giving additional benefit,” he said.
Dr. Lincoff believes these data will lead to a large increase in use of semaglutide, which is already available for the treatment of obesity and diabetes but can be difficult to get reimbursed.
“There is a lot of difficulty getting payors to pay for this drug for weight management. But with this new data from the SELECT trial there should be more willingness – at least in the population with a history of cardiovascular disease,” he commented. In diabetes, where it is already established that there is a cardiovascular risk reduction, it is easier to get these drugs reimbursed, he noted.
On the outcome data, Dr. Lincoff said he could not explain why cardiovascular death was not significantly reduced while all-cause mortality appeared to be cut more definitively.
“The cardiovascular death curves separated, then merged, then separated again. We don’t really know what is going on there. It may be that some deaths were misclassified. This trial was conducted through the COVID era and there may have been less information available on some patients because of that.”
But he added: “The all-cause mortality is more reassuring, as it doesn’t depend on classifying cause of death. Because of the design of the trial, we can’t formally claim a reduction in all-cause mortality, but the results do suggest there is an effect on this endpoint. And all the different types of cardiovascular events were similarly reduced in a consistent way, with similar effects seen across all subgroups. That is very reassuring.”
‘A new era’ for patients with obesity
Outside experts in the field were also impressed with the data.
Designated discussant of the trial at the AHA meeting, Ania Jastreboff, MD, associate professor medicine (endocrinology) at Yale University, New Haven, Conn., said the SELECT trial was “a turning point in the treatment of obesity and a call to action.
“Now is the time to treat obesity to improve health outcomes in people with cardiovascular disease,” she said.
Dr. Jastreboff noted that high BMI was estimated to have accounted for 4 million deaths worldwide in 2015, two-thirds of which were caused by cardiovascular disease. And she presented data showing that U.S. individuals meeting the SELECT criteria increased from 4.3 million in 2011-12 to 6.6 million in 2017-18.
She highlighted one major limitation of the SELECT trial: it enrolled a low number of women (38%) and ethnic minorities, with only 12% of the trial population being Black.
Deepak L. Bhatt, MD, director of Mount Sinai Fuster Heart Hospital, New York, described the SELECT results as “altogether a compelling package of data.”
“These results are even better than I had expected,” Dr. Bhatt said in an interview. “There is a significant reduction in MI as I had anticipated, but additionally, there is a reduction in all-cause death. One can debate the statistics, though on a common-sense level, I think it is a real finding,” he noted.
“Given that MI, heart failure, nephropathy, and revascularization are all reduced, and even stroke is numerically lower, it makes sense that all-cause mortality would be reduced,” he said. “To me, apart from the GI side effects, this counts as a home run.”
Steve Nissen, MD, chief academic officer at the Cleveland Clinic’s Heart, Vascular and Thoracic Institute, was similarly upbeat.
“These data prove what many of us have long suspected – that losing weight can reduce cardiovascular morbidity and mortality. This is great news for patients living with obesity. The obesity epidemic is out of control,” he added. “We need to have therapies that improve cardiovascular outcomes caused by obesity and this shows that semaglutide can do that. I think this is the beginning of a whole new era for patients with obesity.”
Michelle O’Donoghue, MD, associate professor of medicine at Harvard Medical School, Boston, called the results of SELECT “both intriguing and compelling. Certainly, these findings lend further support to the use of semaglutide in a much broader secondary prevention population of individuals with obesity.”
Christie Ballantyne, MD, director of the center for cardiometabolic disease prevention at Baylor College of Medicine, Houston, described the SELECT study as “a landmark trial which will change the practice of medicine in regard to how we treat obesity.”
He compared it with the landmark 4S trial in 1994, the first study in the area of cholesterol lowering therapy to show a clear benefit in reducing cardiovascular events and total mortality, and “began a drastic change in the way that physicians approached treatment of cholesterol.”
On the more robust reduction in all-cause death, compared with cardiovascular death,
Dr. Ballantyne pointed out: “Adjudication of dead or alive is something that everyone gets right. In contrast, the cause of death is sometime difficult to ascertain. Most importantly, the benefit on total mortality also provides assurance that this therapy does not have some adverse effect on increasing noncardiovascular deaths.”
Gastrointestinal adverse effects
On the side effects seen with semaglutide, Dr. Lincoff reported that 10% of patients in the semaglutide group discontinued treatment because of GI side effects versus 2% in the placebo arm. He said this was “an expected issue.”
“GI effects, such as nausea, vomiting and diarrhea, are known side effects of this whole class of drugs. The dose is slowly escalated to manage these adverse effects but there will be a proportion of patients who can’t tolerate it, although the vast majority are able to continue.”
He noted that, while dose reduction was allowed, of the patients who were still on the drug at 2 years, 77% were on the full dose, and 23% were on a reduced dose.
Dr. Lincoff pointed out that there were no serious adverse events with semaglutide. “This is the largest database by far now on the drug with a long-term follow up and we didn’t see the emergence of any new safety signals, which is very reassuring.”
Dr. Nissen said the 16% rate of patients stopping the drug because of tolerability “is not a trivial number.”
He noted that the semaglutide dose used in this study was larger than that used in diabetes.
“They did this to try to achieve more weight loss but then you get more issues with tolerability. It’s a trade-off. If patients are experiencing adverse effects, the dose can be reduced, but then you will lose some effect. All the GLP-1 agonists have GI side effects – it’s part of the way that they work.”
Just weight loss or other actions too?
Speculating on the mechanism behind the reduction in cardiovascular events with semaglutide, Dr. Lincoff does not think it is just weight reduction.
“The event curves start to diverge very soon after the start of the trial and yet the maximum weight loss doesn’t occur until about 65 weeks. I think something else is going on.”
In the paper, the researchers noted that GLP-1 agonists have been shown in animal studies to reduce inflammation, improve endothelial and left ventricular function, promote plaque stability, and decrease platelet aggregation. In this trial, semaglutide was associated with changes in multiple biomarkers of cardiovascular risk, including blood pressure, waist circumference, glycemic control, nephropathy, and levels of lipids and C-reactive protein.
Dr. Lincoff also pointed out that similar benefits were seen in patients with different levels of overweight, and in those who were prediabetic and those who weren’t, so benefit was not dependent on baseline BMI or glycated hemoglobin levels.
Dr. O’Donoghue agreed that other effects, as well as weight loss, could be involved. “The reduction in events with semaglutide appeared very early after initiation and far preceded the drug’s maximal effects on weight reduction. This might suggest that the drug offers other cardioprotective effects through pathways independent of weight loss. Certainly, semaglutide and the other GLP-1 agonists appear to attenuate inflammation, and the patterns of redistribution of adipose tissue may also be of interest.”
She also pointed out that the reduction in cardiovascular events appeared even earlier in this population of obese nondiabetic patients with cardiovascular disease than in prior studies of patients with diabetes. “It may suggest that there is particular benefit for this type of therapy in patients with an inflammatory milieu. I look forward to seeing further analyses to help tease apart the correlation between changes in inflammation, observed weight loss and cardiovascular benefit.”
Effect on clinical practice
With the majority of patients with cardiovascular disease being overweight, these results are obviously going to increase demand for semaglutide, but cost and availability are going to be an issue.
Dr. Bhatt noted that semaglutide is already very popular. “Weight loss drugs are somewhat different from other medications. I can spend 30 minutes trying to convince a patient to take a statin, but here people realize it’s going to cause weight loss and they come in asking for it even if they don’t strictly need it. I think it’s good to have cardiovascular outcome data because now at least for this population of patients, we have evidence to prescribe it.”
He agreed with Dr. Lincoff that these new data should encourage insurance companies to cover the drug, because in reducing cardiovascular events it should also improve downstream health care costs.
“It is providing clear cardiovascular and kidney benefit, so it is in the best interest to the health care system to fund this drug,” he said. “I hope insurers look at it rationally in this way, but they may also be frightened of the explosion of patients wanting this drug and now doctors wanting to prescribe it and how that would affect their shorter-term costs.”
Dr. Lincoff said it would not be easy to prioritize certain groups. “We couldn’t identify any subgroup who showed particularly more benefit than any others. But in the evolution of any therapy, there is a time period where it is in short supply and prohibitively expensive, then over time when there is some competition and pricing deals occur as more people are advocating for it, they become more available.”
‘A welcome treatment option’
In an editorial accompanying publication of the trial, Amit Khera, MD, University of Texas Southwestern Medical Center, Dallas, and Tiffany Powell-Wiley, MD, MPH, National Institutes of Health, Bethesda, noted that baseline risk factors such as LDL cholesterol (78 mg/dL) and systolic blood pressure (131 mm Hg) were not ideal in the semaglutide group in this trial, and they suggest that the benefits of semaglutide may be attenuated when these measures are better controlled.
But given that more than 20 million people in the United States have coronary artery disease, with the majority having overweight or obesity and only approximately 30% having concomitant diabetes, they said that, even in the context of well-controlled risk factors and very low LDL cholesterol levels, the residual risk of atherosclerotic cardiovascular disease in these persons is unacceptably high. “Thus, the SELECT trial provides a welcome treatment option that can be extended to millions of additional patients.”
However, the editorialists cautioned that semaglutide at current pricing comes with a significant cost to both patients and society, which makes this treatment inaccessible for many.
They added that intensive lifestyle interventions and bariatric surgery remain effective but underutilized options for obesity, and that the prevention of obesity before it develops should be the primary goal.
The SELECT trial was supported by Novo Nordisk, and several coauthors are employees of the company. Dr. Lincoff is a consultant for Novo Nordisk. Dr. Bhatt and Dr. Nissen are involved in a cardiovascular outcomes trial with a new investigational weight loss drug from Lilly. Dr. Bhatt and Dr. Ballantyne are also investigators in a Novo Nordisk trial of a new anti-inflammatory drug.
FROM AHA 2023
Angioplasty finally proven beneficial in stable angina: ORBITA-2
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.
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.
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.
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.
AT AHA 2023
In MI with anemia, results may favor liberal transfusion: MINT
In patients with myocardial infarction and anemia, a “liberal” red blood cell transfusion strategy did not significantly reduce the risk of recurrent MI or death within 30 days, compared with a “restrictive” transfusion strategy, in the 3,500-patient MINT trial.
Jeffrey L. Carson, MD, from Robert Wood Johnson Medical School, New Brunswick, N.J., said in a press briefing.
He presented the study in a late-breaking trial session at the annual scientific sessions of the American Heart Association, and it was simultaneously published online in the New England Journal of Medicine.
“Whether to transfuse is an everyday decision faced by clinicians caring for patients with acute MI,” Dr. Carson said.
“We cannot claim that a liberal transfusion strategy is definitively superior based on our primary outcome,” he said, but “the 95% confidence interval is consistent with treatment effects corresponding to no difference between the two transfusion strategies and to a clinically relevant benefit with the liberal strategy.”
“In contrast to other trials in other settings,” such as anemia and cardiac surgery, Dr. Carson said, “the results suggest that a liberal transfusion strategy has the potential for clinical benefit with an acceptable risk of harm.”
“A liberal transfusion strategy may be the most prudent approach to transfusion in anemic patients with MI,” he added.
Not a home run
Others agreed with this interpretation. Martin B. Leon, MD, from Columbia University, New York, the study discussant in the press briefing, said the study “addresses a question that is common” in clinical practice. It was well conducted, and international (although most patients were in the United States and Canada), in a very broad group of patients, designed to make the results more generalizable. The 98% follow-up was extremely good, Dr. Leon added, and the trialists achieved their goal in that they did show a difference between the two transfusion strategies.
The number needed to treat was 40 to see a benefit in the combined outcome of death or recurrent MI at 30 days, Dr. Leon said. The P value for this was .07, “right on the edge” of statistical significance.
This study is “not a home run,” for the primary outcome, he noted; however, many of the outcomes tended to be in favor of a liberal transfusion strategy. Notably, cardiovascular death, which was not a specified outcome, was significantly lower in the group who received a liberal transfusion strategy.
Although a liberal transfusion strategy was “not definitely superior” in these patients with MI and anemia, Dr. Carson said, he thinks the trial will be interpreted as favoring a liberal transfusion strategy.
C. Michael Gibson, MD, professor of medicine at Harvard Medical School, Boston, and CEO of Harvard’s Baim and PERFUSE institutes for clinical research, voiced similar views.
“Given the lack of acute harm associated with liberal transfusion and the preponderance of evidence favoring liberal transfusion in the largest trial to date,” concluded Dr. Gibson, the assigned discussant at the session, “liberal transfusion appears to be a viable management strategy, particularly among patients with non-STEMI type 1 MI and as clinical judgment dictates.”
Only three small randomized controlled trials have compared transfusion thresholds in a total of 820 patients with MI and anemia, Dr. Gibson said, a point that the trial investigators also made. The results were inconsistent between trials: the CRIT trial (n = 45) favored a restrictive strategy, the MINT pilot study (n = 110) favored a liberal one, and the REALITY trial (n = 668) showed noninferiority of a restrictive strategy, compared with a liberal strategy in 30-day MACE.
The MINT trial was four times larger than all prior studies combined. However, most outcomes were negative or of borderline significance for benefit.
Cardiac death was more common in the restrictive group at 5.5% than the liberal group at 3.2% (risk ratio, 1.74, 95% CI, 1.26-2.40), but this was nonadjudicated, and not designated as a primary, secondary, or tertiary outcome – which the researchers also noted. Fewer than half of the deaths were classified as cardiac, which was “odd,” Dr. Gibson observed.
A restrictive transfusion strategy was associated with increased events among participants with type 1 MI (RR, 1.32, 95% CI, 1.04-1.67), he noted.
Study strengths included that 45.5% of participants were women, Dr. Gibson said. Limitations included that the trial was “somewhat underpowered.” Also, even in the restrictive group, participants received a mean of 0.7 units of packed red blood cells.
Adherence to the 10 g/dL threshold in the liberal transfusion group was moderate (86.3% at hospital discharge), which the researchers acknowledged. They noted that this was frequently caused by clinical discretion, such as concern about fluid overload, and to the timing of hospital discharge. In addition, long-term potential for harm (microchimerism) is not known.
“There was a consistent nonsignificant acute benefit for liberal transfusion and a nominal reduction in CV mortality and improved outcomes in patients with type 1 MI in exploratory analyses, in a trial that ended up underpowered,” Dr. Gibson summarized. “Long-term follow up would be helpful to evaluate chronic outcomes.”
This is a very well-conducted, high-quality, important study that will be considered a landmark trial, C. David Mazer, MD, University of Toronto and St. Michael’s Hospital, also in Toronto, said in an interview.
Unfortunately, “it was not as definitive as hoped for,” Dr. Mazer lamented. Nevertheless, “I think people may interpret it as providing support for a liberal transfusion strategy” in patients with anemia and MI, he said.
Dr. Mazer, who was not involved with this research, was a principal investigator on the TRICS-3 trial, which disputed a liberal RBC transfusion strategy in patients with anemia undergoing cardiac surgery, as previously reported.
The “Red Blood Cell Transfusion: 2023 AABB International Guidelines,” led by Dr. Carson and published in JAMA, recommend a restrictive strategy in stable patients, although these guidelines did not include the current study, Dr. Mazer observed.
In the REALITY trial, there were fewer major adverse cardiac events (MACE) events in the restrictive strategy, he noted.
MINT can be viewed as comparing a high versus low hemoglobin threshold. “It is possible that the best is in between,” he said.
Dr. Mazer also noted that MINT may have achieved significance if it was designed with a larger enrollment and a higher power (for example, 90% instead of 80%) to detect between-group difference for the primary outcome.
Study rationale, design, and findings
Anemia, or low RBC count, is common in patients with MI, Dr. Carson noted. A normal hemoglobin is 13 g/dL in men and 12 g/dL in women. Administering a packed RBC transfusion only when a patient’s hemoglobin falls below 7 or 8 g/dL has been widely adopted, but it is unclear if patients with acute MI may benefit from a higher hemoglobin level.
“Blood transfusion may decrease ischemic injury by improving oxygen delivery to myocardial tissues and reduce the risk of reinfarction or death,” the researchers wrote. “Alternatively, administering more blood could result in more frequent heart failure from fluid overload, infection from immunosuppression, thrombosis from higher viscosity, and inflammation.”
From 2017 to 2023, investigators enrolled 3,504 adults aged 18 and older at 144 sites in the United States (2,157 patients), Canada (885), France (323), Brazil (105), New Zealand (25), and Australia (9).
The participants had ST-elevation or non–ST-elevation MI and hemoglobin less than 10 g/dL within 24 hours. Patients with type 1 (atherosclerotic plaque disruption), type 2 (supply-demand mismatch without atherothrombotic plaque disruption), type 4b, or type 4c MI were eligible.
They were randomly assigned to receive:
- A ‘restrictive’ transfusion strategy (1,749 patients): Transfusion was permitted but not required when a patient’s hemoglobin was less than 8 g/dL and was strongly recommended when it was less than 7 g/dL or when anginal symptoms were not controlled with medications.
- A ‘liberal’ transfusion strategy (1,755 patients): One unit of RBCs was administered after randomization, and RBCs were transfused to maintain hemoglobin 10 g/dL or higher until hospital discharge or 30 days.
The patients had a mean age of 72 years and 46% were women. More than three-quarters (78%) were White and 14% were Black. They had frequent coexisting illnesses, about a third had a history of MI, percutaneous coronary intervention, or heart failure; 14% were on a ventilator and 12% had renal dialysis. The median duration of hospitalization was 5 days in the two groups.
At baseline, the mean hemoglobin was 8.6 g/dL in both groups. At days 1, 2, and 3, the mean hemoglobin was 8.8, 8.9, and 8.9 g/dL, respectively, in the restrictive transfusion group, and 10.1, 10.4, and 10.5 g/dL, respectively, in the liberal transfusion group.
The mean number of transfused blood units was 0.7 units in the restrictive strategy group and 2.5 units in the liberal strategy group, roughly a 3.5-fold difference.
After adjustment for site and incomplete follow-up in 57 patients (20 with the restrictive strategy and 37 with the liberal strategy), the estimated RR for the primary outcome in the restrictive group versus the liberal group was 1.15 (P = .07).
“We observed that the 95% confidence interval contains values that suggest a clinical benefit for the liberal transfusion strategy and does not include values that suggest a benefit for the more restrictive transfusion strategy,” the researchers wrote. Heart failure and other safety outcomes were comparable in the two groups.
The trial was supported by grants from the National Heart, Lung, and Blood Institute and by the Canadian Blood Services and Canadian Institutes of Health Research Institute of Circulatory and Respiratory Health. Dr. Carson, Dr. Leon, Dr. Gibson, and Dr. Mazer reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In patients with myocardial infarction and anemia, a “liberal” red blood cell transfusion strategy did not significantly reduce the risk of recurrent MI or death within 30 days, compared with a “restrictive” transfusion strategy, in the 3,500-patient MINT trial.
Jeffrey L. Carson, MD, from Robert Wood Johnson Medical School, New Brunswick, N.J., said in a press briefing.
He presented the study in a late-breaking trial session at the annual scientific sessions of the American Heart Association, and it was simultaneously published online in the New England Journal of Medicine.
“Whether to transfuse is an everyday decision faced by clinicians caring for patients with acute MI,” Dr. Carson said.
“We cannot claim that a liberal transfusion strategy is definitively superior based on our primary outcome,” he said, but “the 95% confidence interval is consistent with treatment effects corresponding to no difference between the two transfusion strategies and to a clinically relevant benefit with the liberal strategy.”
“In contrast to other trials in other settings,” such as anemia and cardiac surgery, Dr. Carson said, “the results suggest that a liberal transfusion strategy has the potential for clinical benefit with an acceptable risk of harm.”
“A liberal transfusion strategy may be the most prudent approach to transfusion in anemic patients with MI,” he added.
Not a home run
Others agreed with this interpretation. Martin B. Leon, MD, from Columbia University, New York, the study discussant in the press briefing, said the study “addresses a question that is common” in clinical practice. It was well conducted, and international (although most patients were in the United States and Canada), in a very broad group of patients, designed to make the results more generalizable. The 98% follow-up was extremely good, Dr. Leon added, and the trialists achieved their goal in that they did show a difference between the two transfusion strategies.
The number needed to treat was 40 to see a benefit in the combined outcome of death or recurrent MI at 30 days, Dr. Leon said. The P value for this was .07, “right on the edge” of statistical significance.
This study is “not a home run,” for the primary outcome, he noted; however, many of the outcomes tended to be in favor of a liberal transfusion strategy. Notably, cardiovascular death, which was not a specified outcome, was significantly lower in the group who received a liberal transfusion strategy.
Although a liberal transfusion strategy was “not definitely superior” in these patients with MI and anemia, Dr. Carson said, he thinks the trial will be interpreted as favoring a liberal transfusion strategy.
C. Michael Gibson, MD, professor of medicine at Harvard Medical School, Boston, and CEO of Harvard’s Baim and PERFUSE institutes for clinical research, voiced similar views.
“Given the lack of acute harm associated with liberal transfusion and the preponderance of evidence favoring liberal transfusion in the largest trial to date,” concluded Dr. Gibson, the assigned discussant at the session, “liberal transfusion appears to be a viable management strategy, particularly among patients with non-STEMI type 1 MI and as clinical judgment dictates.”
Only three small randomized controlled trials have compared transfusion thresholds in a total of 820 patients with MI and anemia, Dr. Gibson said, a point that the trial investigators also made. The results were inconsistent between trials: the CRIT trial (n = 45) favored a restrictive strategy, the MINT pilot study (n = 110) favored a liberal one, and the REALITY trial (n = 668) showed noninferiority of a restrictive strategy, compared with a liberal strategy in 30-day MACE.
The MINT trial was four times larger than all prior studies combined. However, most outcomes were negative or of borderline significance for benefit.
Cardiac death was more common in the restrictive group at 5.5% than the liberal group at 3.2% (risk ratio, 1.74, 95% CI, 1.26-2.40), but this was nonadjudicated, and not designated as a primary, secondary, or tertiary outcome – which the researchers also noted. Fewer than half of the deaths were classified as cardiac, which was “odd,” Dr. Gibson observed.
A restrictive transfusion strategy was associated with increased events among participants with type 1 MI (RR, 1.32, 95% CI, 1.04-1.67), he noted.
Study strengths included that 45.5% of participants were women, Dr. Gibson said. Limitations included that the trial was “somewhat underpowered.” Also, even in the restrictive group, participants received a mean of 0.7 units of packed red blood cells.
Adherence to the 10 g/dL threshold in the liberal transfusion group was moderate (86.3% at hospital discharge), which the researchers acknowledged. They noted that this was frequently caused by clinical discretion, such as concern about fluid overload, and to the timing of hospital discharge. In addition, long-term potential for harm (microchimerism) is not known.
“There was a consistent nonsignificant acute benefit for liberal transfusion and a nominal reduction in CV mortality and improved outcomes in patients with type 1 MI in exploratory analyses, in a trial that ended up underpowered,” Dr. Gibson summarized. “Long-term follow up would be helpful to evaluate chronic outcomes.”
This is a very well-conducted, high-quality, important study that will be considered a landmark trial, C. David Mazer, MD, University of Toronto and St. Michael’s Hospital, also in Toronto, said in an interview.
Unfortunately, “it was not as definitive as hoped for,” Dr. Mazer lamented. Nevertheless, “I think people may interpret it as providing support for a liberal transfusion strategy” in patients with anemia and MI, he said.
Dr. Mazer, who was not involved with this research, was a principal investigator on the TRICS-3 trial, which disputed a liberal RBC transfusion strategy in patients with anemia undergoing cardiac surgery, as previously reported.
The “Red Blood Cell Transfusion: 2023 AABB International Guidelines,” led by Dr. Carson and published in JAMA, recommend a restrictive strategy in stable patients, although these guidelines did not include the current study, Dr. Mazer observed.
In the REALITY trial, there were fewer major adverse cardiac events (MACE) events in the restrictive strategy, he noted.
MINT can be viewed as comparing a high versus low hemoglobin threshold. “It is possible that the best is in between,” he said.
Dr. Mazer also noted that MINT may have achieved significance if it was designed with a larger enrollment and a higher power (for example, 90% instead of 80%) to detect between-group difference for the primary outcome.
Study rationale, design, and findings
Anemia, or low RBC count, is common in patients with MI, Dr. Carson noted. A normal hemoglobin is 13 g/dL in men and 12 g/dL in women. Administering a packed RBC transfusion only when a patient’s hemoglobin falls below 7 or 8 g/dL has been widely adopted, but it is unclear if patients with acute MI may benefit from a higher hemoglobin level.
“Blood transfusion may decrease ischemic injury by improving oxygen delivery to myocardial tissues and reduce the risk of reinfarction or death,” the researchers wrote. “Alternatively, administering more blood could result in more frequent heart failure from fluid overload, infection from immunosuppression, thrombosis from higher viscosity, and inflammation.”
From 2017 to 2023, investigators enrolled 3,504 adults aged 18 and older at 144 sites in the United States (2,157 patients), Canada (885), France (323), Brazil (105), New Zealand (25), and Australia (9).
The participants had ST-elevation or non–ST-elevation MI and hemoglobin less than 10 g/dL within 24 hours. Patients with type 1 (atherosclerotic plaque disruption), type 2 (supply-demand mismatch without atherothrombotic plaque disruption), type 4b, or type 4c MI were eligible.
They were randomly assigned to receive:
- A ‘restrictive’ transfusion strategy (1,749 patients): Transfusion was permitted but not required when a patient’s hemoglobin was less than 8 g/dL and was strongly recommended when it was less than 7 g/dL or when anginal symptoms were not controlled with medications.
- A ‘liberal’ transfusion strategy (1,755 patients): One unit of RBCs was administered after randomization, and RBCs were transfused to maintain hemoglobin 10 g/dL or higher until hospital discharge or 30 days.
The patients had a mean age of 72 years and 46% were women. More than three-quarters (78%) were White and 14% were Black. They had frequent coexisting illnesses, about a third had a history of MI, percutaneous coronary intervention, or heart failure; 14% were on a ventilator and 12% had renal dialysis. The median duration of hospitalization was 5 days in the two groups.
At baseline, the mean hemoglobin was 8.6 g/dL in both groups. At days 1, 2, and 3, the mean hemoglobin was 8.8, 8.9, and 8.9 g/dL, respectively, in the restrictive transfusion group, and 10.1, 10.4, and 10.5 g/dL, respectively, in the liberal transfusion group.
The mean number of transfused blood units was 0.7 units in the restrictive strategy group and 2.5 units in the liberal strategy group, roughly a 3.5-fold difference.
After adjustment for site and incomplete follow-up in 57 patients (20 with the restrictive strategy and 37 with the liberal strategy), the estimated RR for the primary outcome in the restrictive group versus the liberal group was 1.15 (P = .07).
“We observed that the 95% confidence interval contains values that suggest a clinical benefit for the liberal transfusion strategy and does not include values that suggest a benefit for the more restrictive transfusion strategy,” the researchers wrote. Heart failure and other safety outcomes were comparable in the two groups.
The trial was supported by grants from the National Heart, Lung, and Blood Institute and by the Canadian Blood Services and Canadian Institutes of Health Research Institute of Circulatory and Respiratory Health. Dr. Carson, Dr. Leon, Dr. Gibson, and Dr. Mazer reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In patients with myocardial infarction and anemia, a “liberal” red blood cell transfusion strategy did not significantly reduce the risk of recurrent MI or death within 30 days, compared with a “restrictive” transfusion strategy, in the 3,500-patient MINT trial.
Jeffrey L. Carson, MD, from Robert Wood Johnson Medical School, New Brunswick, N.J., said in a press briefing.
He presented the study in a late-breaking trial session at the annual scientific sessions of the American Heart Association, and it was simultaneously published online in the New England Journal of Medicine.
“Whether to transfuse is an everyday decision faced by clinicians caring for patients with acute MI,” Dr. Carson said.
“We cannot claim that a liberal transfusion strategy is definitively superior based on our primary outcome,” he said, but “the 95% confidence interval is consistent with treatment effects corresponding to no difference between the two transfusion strategies and to a clinically relevant benefit with the liberal strategy.”
“In contrast to other trials in other settings,” such as anemia and cardiac surgery, Dr. Carson said, “the results suggest that a liberal transfusion strategy has the potential for clinical benefit with an acceptable risk of harm.”
“A liberal transfusion strategy may be the most prudent approach to transfusion in anemic patients with MI,” he added.
Not a home run
Others agreed with this interpretation. Martin B. Leon, MD, from Columbia University, New York, the study discussant in the press briefing, said the study “addresses a question that is common” in clinical practice. It was well conducted, and international (although most patients were in the United States and Canada), in a very broad group of patients, designed to make the results more generalizable. The 98% follow-up was extremely good, Dr. Leon added, and the trialists achieved their goal in that they did show a difference between the two transfusion strategies.
The number needed to treat was 40 to see a benefit in the combined outcome of death or recurrent MI at 30 days, Dr. Leon said. The P value for this was .07, “right on the edge” of statistical significance.
This study is “not a home run,” for the primary outcome, he noted; however, many of the outcomes tended to be in favor of a liberal transfusion strategy. Notably, cardiovascular death, which was not a specified outcome, was significantly lower in the group who received a liberal transfusion strategy.
Although a liberal transfusion strategy was “not definitely superior” in these patients with MI and anemia, Dr. Carson said, he thinks the trial will be interpreted as favoring a liberal transfusion strategy.
C. Michael Gibson, MD, professor of medicine at Harvard Medical School, Boston, and CEO of Harvard’s Baim and PERFUSE institutes for clinical research, voiced similar views.
“Given the lack of acute harm associated with liberal transfusion and the preponderance of evidence favoring liberal transfusion in the largest trial to date,” concluded Dr. Gibson, the assigned discussant at the session, “liberal transfusion appears to be a viable management strategy, particularly among patients with non-STEMI type 1 MI and as clinical judgment dictates.”
Only three small randomized controlled trials have compared transfusion thresholds in a total of 820 patients with MI and anemia, Dr. Gibson said, a point that the trial investigators also made. The results were inconsistent between trials: the CRIT trial (n = 45) favored a restrictive strategy, the MINT pilot study (n = 110) favored a liberal one, and the REALITY trial (n = 668) showed noninferiority of a restrictive strategy, compared with a liberal strategy in 30-day MACE.
The MINT trial was four times larger than all prior studies combined. However, most outcomes were negative or of borderline significance for benefit.
Cardiac death was more common in the restrictive group at 5.5% than the liberal group at 3.2% (risk ratio, 1.74, 95% CI, 1.26-2.40), but this was nonadjudicated, and not designated as a primary, secondary, or tertiary outcome – which the researchers also noted. Fewer than half of the deaths were classified as cardiac, which was “odd,” Dr. Gibson observed.
A restrictive transfusion strategy was associated with increased events among participants with type 1 MI (RR, 1.32, 95% CI, 1.04-1.67), he noted.
Study strengths included that 45.5% of participants were women, Dr. Gibson said. Limitations included that the trial was “somewhat underpowered.” Also, even in the restrictive group, participants received a mean of 0.7 units of packed red blood cells.
Adherence to the 10 g/dL threshold in the liberal transfusion group was moderate (86.3% at hospital discharge), which the researchers acknowledged. They noted that this was frequently caused by clinical discretion, such as concern about fluid overload, and to the timing of hospital discharge. In addition, long-term potential for harm (microchimerism) is not known.
“There was a consistent nonsignificant acute benefit for liberal transfusion and a nominal reduction in CV mortality and improved outcomes in patients with type 1 MI in exploratory analyses, in a trial that ended up underpowered,” Dr. Gibson summarized. “Long-term follow up would be helpful to evaluate chronic outcomes.”
This is a very well-conducted, high-quality, important study that will be considered a landmark trial, C. David Mazer, MD, University of Toronto and St. Michael’s Hospital, also in Toronto, said in an interview.
Unfortunately, “it was not as definitive as hoped for,” Dr. Mazer lamented. Nevertheless, “I think people may interpret it as providing support for a liberal transfusion strategy” in patients with anemia and MI, he said.
Dr. Mazer, who was not involved with this research, was a principal investigator on the TRICS-3 trial, which disputed a liberal RBC transfusion strategy in patients with anemia undergoing cardiac surgery, as previously reported.
The “Red Blood Cell Transfusion: 2023 AABB International Guidelines,” led by Dr. Carson and published in JAMA, recommend a restrictive strategy in stable patients, although these guidelines did not include the current study, Dr. Mazer observed.
In the REALITY trial, there were fewer major adverse cardiac events (MACE) events in the restrictive strategy, he noted.
MINT can be viewed as comparing a high versus low hemoglobin threshold. “It is possible that the best is in between,” he said.
Dr. Mazer also noted that MINT may have achieved significance if it was designed with a larger enrollment and a higher power (for example, 90% instead of 80%) to detect between-group difference for the primary outcome.
Study rationale, design, and findings
Anemia, or low RBC count, is common in patients with MI, Dr. Carson noted. A normal hemoglobin is 13 g/dL in men and 12 g/dL in women. Administering a packed RBC transfusion only when a patient’s hemoglobin falls below 7 or 8 g/dL has been widely adopted, but it is unclear if patients with acute MI may benefit from a higher hemoglobin level.
“Blood transfusion may decrease ischemic injury by improving oxygen delivery to myocardial tissues and reduce the risk of reinfarction or death,” the researchers wrote. “Alternatively, administering more blood could result in more frequent heart failure from fluid overload, infection from immunosuppression, thrombosis from higher viscosity, and inflammation.”
From 2017 to 2023, investigators enrolled 3,504 adults aged 18 and older at 144 sites in the United States (2,157 patients), Canada (885), France (323), Brazil (105), New Zealand (25), and Australia (9).
The participants had ST-elevation or non–ST-elevation MI and hemoglobin less than 10 g/dL within 24 hours. Patients with type 1 (atherosclerotic plaque disruption), type 2 (supply-demand mismatch without atherothrombotic plaque disruption), type 4b, or type 4c MI were eligible.
They were randomly assigned to receive:
- A ‘restrictive’ transfusion strategy (1,749 patients): Transfusion was permitted but not required when a patient’s hemoglobin was less than 8 g/dL and was strongly recommended when it was less than 7 g/dL or when anginal symptoms were not controlled with medications.
- A ‘liberal’ transfusion strategy (1,755 patients): One unit of RBCs was administered after randomization, and RBCs were transfused to maintain hemoglobin 10 g/dL or higher until hospital discharge or 30 days.
The patients had a mean age of 72 years and 46% were women. More than three-quarters (78%) were White and 14% were Black. They had frequent coexisting illnesses, about a third had a history of MI, percutaneous coronary intervention, or heart failure; 14% were on a ventilator and 12% had renal dialysis. The median duration of hospitalization was 5 days in the two groups.
At baseline, the mean hemoglobin was 8.6 g/dL in both groups. At days 1, 2, and 3, the mean hemoglobin was 8.8, 8.9, and 8.9 g/dL, respectively, in the restrictive transfusion group, and 10.1, 10.4, and 10.5 g/dL, respectively, in the liberal transfusion group.
The mean number of transfused blood units was 0.7 units in the restrictive strategy group and 2.5 units in the liberal strategy group, roughly a 3.5-fold difference.
After adjustment for site and incomplete follow-up in 57 patients (20 with the restrictive strategy and 37 with the liberal strategy), the estimated RR for the primary outcome in the restrictive group versus the liberal group was 1.15 (P = .07).
“We observed that the 95% confidence interval contains values that suggest a clinical benefit for the liberal transfusion strategy and does not include values that suggest a benefit for the more restrictive transfusion strategy,” the researchers wrote. Heart failure and other safety outcomes were comparable in the two groups.
The trial was supported by grants from the National Heart, Lung, and Blood Institute and by the Canadian Blood Services and Canadian Institutes of Health Research Institute of Circulatory and Respiratory Health. Dr. Carson, Dr. Leon, Dr. Gibson, and Dr. Mazer reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM AHA 2023
Prurigo nodularis diagnosis delay in skin of color gains added significance
NEW YORK – 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.”
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 – 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.”
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 – 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.”
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.
AT SOC 2023
Gout: Studies support early use of urate-lowering therapy, warn of peripheral arterial disease
LA JOLLA, Calif. – A new analysis suggests that it may not be necessary to delay urate-lowering therapy (ULT) in gout flares, and a study warns of the potential heightened risk of peripheral arterial disease (PAD) in gout.
The reports were released at the annual research symposium of the Gout, Hyperuricemia, and Crystal Associated Disease Network (G-CAN).
The urate-lowering report, a systematic review and meta-analysis, suggests that the use of ULT during a gout flare “does not affect flare severity nor the duration of the flare or risk of recurrence in the subsequent month,” lead author Vicky Tai, MBChB, of the University of Auckland (New Zealand), said in a presentation.
She noted that there’s ongoing debate about whether ULT should be delayed until a week or two after gout flares subside to avoid their return. “This is reflected in guidelines on gout management, which have provided inconsistent recommendations on the issue,” Dr. Tai said.
As she noted, the American College of Rheumatology’s 2020 gout guidelines conditionally recommended starting ULT during gout flares – and not afterward – if it’s indicated. (The guidelines also conditionally recommend against ULT in a first gout flare, however, with a few exceptions.)
The British Society for Rheumatology’s 2017 gout guidelines suggested waiting until flares have settled down and “the patient was no longer in pain,” although ULT may be started in patients with frequent attacks. The European Alliance of Associations for Rheumatology’s gout guidelines from 2016 didn’t address timing, Dr. Tai said.
For the new analysis, Dr. Tai and colleagues examined six randomized studies from the United States (two), China (two), Taiwan (one), and Thailand (one) that examined the use of allopurinol (three studies), febuxostat (two studies), and probenecid (one). The studies, dated from 2012 to 2023, randomized 226 subjects with gout to early initiation of ULT vs. 219 who received placebo or delayed ULT. Subjects were tracked for a median of 28 days (15 days to 12 weeks).
Three of the studies were deemed to have high risk of bias.
There were no differences in patient-rated pain scores at various time points, duration of gout flares (examined in three studies), or recurrence of gout flares (examined in four studies).
“Other outcomes of interest, including long-term adherence, time to achieve target serum urate, and patient satisfaction with treatment, were not examined,” Dr. Tai said. “Adverse events were similar between groups.”
She cautioned that the sample sizes are small, and the findings may not be applicable to patients with tophaceous gout or comorbid renal disease.
A similar meta-analysis published in 2022 examined five studies (including three of those in the new analysis); among the five was one study from 1987 that examined azapropazone and indomethacin plus allopurinol. The review found “that initiation of ULT during an acute gout flare did not prolong the duration of acute flares.”
Risk for PAD
In the other study, researchers raised an alarm after finding a high rate of PAD in patients with gout regardless of whether they also had diabetes, which is a known risk factor for PAD. “Our data suggest that gout is an underrecognized risk factor for PAD and indicates the importance of assessing for PAD in gout patients,” lead author Nicole Leung, MD, of NYU Langone Health, said in a presentation.
According to Dr. Leung, there’s little known about links between PAD and gout, although she highlighted a 2018 study that found that patients with obstructive coronary artery disease were more likely to have poor outcomes if they also developed gout after catheterization. She highlighted a 2022 study that found higher rates of lower-extremity amputations in patients with gout independent of cardiovascular disease and diabetes. However, she noted that a link to PAD is unclear, and the study found a link between gout and amputations that was independent of PAD.
Patients with gout, she added, are not routinely screened for PAD.
For the new retrospective, cross-sectional analysis, Dr. Leung and colleagues examined Veterans Administration data from 2014 to 2018 for 7.2 million patients. The population was largely male.
Of those, 140,862 (2.52%) – the control group – had no gout or diabetes. In comparison, 11,449 (5.56%) of 205,904 with gout but not diabetes had PAD, for a rate 2.2 times greater than the control group). PAD occurred in 101,582 (8.70%) of 1,168,138 with diabetes but not gout, giving a rate 3.2 times greater than the control group. The rate was highest among people with both gout and diabetes, at 9.97% (9,905 of 99,377), which is about four times greater than the control group.
The link between gout and PAD remained after adjustment for creatinine levels, age, gender, and body mass index. Diabetes was linked to a higher risk for PAD than was gout, and the effect of both conditions combined was “less than additive.” This “may suggest an overlap and pathophysiology between the two,” she said.
Disclosure information was not provided. The Rheumatology Research Foundation funded the PAD study; funding information for the ULT/gout flare analysis was not provided.
LA JOLLA, Calif. – A new analysis suggests that it may not be necessary to delay urate-lowering therapy (ULT) in gout flares, and a study warns of the potential heightened risk of peripheral arterial disease (PAD) in gout.
The reports were released at the annual research symposium of the Gout, Hyperuricemia, and Crystal Associated Disease Network (G-CAN).
The urate-lowering report, a systematic review and meta-analysis, suggests that the use of ULT during a gout flare “does not affect flare severity nor the duration of the flare or risk of recurrence in the subsequent month,” lead author Vicky Tai, MBChB, of the University of Auckland (New Zealand), said in a presentation.
She noted that there’s ongoing debate about whether ULT should be delayed until a week or two after gout flares subside to avoid their return. “This is reflected in guidelines on gout management, which have provided inconsistent recommendations on the issue,” Dr. Tai said.
As she noted, the American College of Rheumatology’s 2020 gout guidelines conditionally recommended starting ULT during gout flares – and not afterward – if it’s indicated. (The guidelines also conditionally recommend against ULT in a first gout flare, however, with a few exceptions.)
The British Society for Rheumatology’s 2017 gout guidelines suggested waiting until flares have settled down and “the patient was no longer in pain,” although ULT may be started in patients with frequent attacks. The European Alliance of Associations for Rheumatology’s gout guidelines from 2016 didn’t address timing, Dr. Tai said.
For the new analysis, Dr. Tai and colleagues examined six randomized studies from the United States (two), China (two), Taiwan (one), and Thailand (one) that examined the use of allopurinol (three studies), febuxostat (two studies), and probenecid (one). The studies, dated from 2012 to 2023, randomized 226 subjects with gout to early initiation of ULT vs. 219 who received placebo or delayed ULT. Subjects were tracked for a median of 28 days (15 days to 12 weeks).
Three of the studies were deemed to have high risk of bias.
There were no differences in patient-rated pain scores at various time points, duration of gout flares (examined in three studies), or recurrence of gout flares (examined in four studies).
“Other outcomes of interest, including long-term adherence, time to achieve target serum urate, and patient satisfaction with treatment, were not examined,” Dr. Tai said. “Adverse events were similar between groups.”
She cautioned that the sample sizes are small, and the findings may not be applicable to patients with tophaceous gout or comorbid renal disease.
A similar meta-analysis published in 2022 examined five studies (including three of those in the new analysis); among the five was one study from 1987 that examined azapropazone and indomethacin plus allopurinol. The review found “that initiation of ULT during an acute gout flare did not prolong the duration of acute flares.”
Risk for PAD
In the other study, researchers raised an alarm after finding a high rate of PAD in patients with gout regardless of whether they also had diabetes, which is a known risk factor for PAD. “Our data suggest that gout is an underrecognized risk factor for PAD and indicates the importance of assessing for PAD in gout patients,” lead author Nicole Leung, MD, of NYU Langone Health, said in a presentation.
According to Dr. Leung, there’s little known about links between PAD and gout, although she highlighted a 2018 study that found that patients with obstructive coronary artery disease were more likely to have poor outcomes if they also developed gout after catheterization. She highlighted a 2022 study that found higher rates of lower-extremity amputations in patients with gout independent of cardiovascular disease and diabetes. However, she noted that a link to PAD is unclear, and the study found a link between gout and amputations that was independent of PAD.
Patients with gout, she added, are not routinely screened for PAD.
For the new retrospective, cross-sectional analysis, Dr. Leung and colleagues examined Veterans Administration data from 2014 to 2018 for 7.2 million patients. The population was largely male.
Of those, 140,862 (2.52%) – the control group – had no gout or diabetes. In comparison, 11,449 (5.56%) of 205,904 with gout but not diabetes had PAD, for a rate 2.2 times greater than the control group). PAD occurred in 101,582 (8.70%) of 1,168,138 with diabetes but not gout, giving a rate 3.2 times greater than the control group. The rate was highest among people with both gout and diabetes, at 9.97% (9,905 of 99,377), which is about four times greater than the control group.
The link between gout and PAD remained after adjustment for creatinine levels, age, gender, and body mass index. Diabetes was linked to a higher risk for PAD than was gout, and the effect of both conditions combined was “less than additive.” This “may suggest an overlap and pathophysiology between the two,” she said.
Disclosure information was not provided. The Rheumatology Research Foundation funded the PAD study; funding information for the ULT/gout flare analysis was not provided.
LA JOLLA, Calif. – A new analysis suggests that it may not be necessary to delay urate-lowering therapy (ULT) in gout flares, and a study warns of the potential heightened risk of peripheral arterial disease (PAD) in gout.
The reports were released at the annual research symposium of the Gout, Hyperuricemia, and Crystal Associated Disease Network (G-CAN).
The urate-lowering report, a systematic review and meta-analysis, suggests that the use of ULT during a gout flare “does not affect flare severity nor the duration of the flare or risk of recurrence in the subsequent month,” lead author Vicky Tai, MBChB, of the University of Auckland (New Zealand), said in a presentation.
She noted that there’s ongoing debate about whether ULT should be delayed until a week or two after gout flares subside to avoid their return. “This is reflected in guidelines on gout management, which have provided inconsistent recommendations on the issue,” Dr. Tai said.
As she noted, the American College of Rheumatology’s 2020 gout guidelines conditionally recommended starting ULT during gout flares – and not afterward – if it’s indicated. (The guidelines also conditionally recommend against ULT in a first gout flare, however, with a few exceptions.)
The British Society for Rheumatology’s 2017 gout guidelines suggested waiting until flares have settled down and “the patient was no longer in pain,” although ULT may be started in patients with frequent attacks. The European Alliance of Associations for Rheumatology’s gout guidelines from 2016 didn’t address timing, Dr. Tai said.
For the new analysis, Dr. Tai and colleagues examined six randomized studies from the United States (two), China (two), Taiwan (one), and Thailand (one) that examined the use of allopurinol (three studies), febuxostat (two studies), and probenecid (one). The studies, dated from 2012 to 2023, randomized 226 subjects with gout to early initiation of ULT vs. 219 who received placebo or delayed ULT. Subjects were tracked for a median of 28 days (15 days to 12 weeks).
Three of the studies were deemed to have high risk of bias.
There were no differences in patient-rated pain scores at various time points, duration of gout flares (examined in three studies), or recurrence of gout flares (examined in four studies).
“Other outcomes of interest, including long-term adherence, time to achieve target serum urate, and patient satisfaction with treatment, were not examined,” Dr. Tai said. “Adverse events were similar between groups.”
She cautioned that the sample sizes are small, and the findings may not be applicable to patients with tophaceous gout or comorbid renal disease.
A similar meta-analysis published in 2022 examined five studies (including three of those in the new analysis); among the five was one study from 1987 that examined azapropazone and indomethacin plus allopurinol. The review found “that initiation of ULT during an acute gout flare did not prolong the duration of acute flares.”
Risk for PAD
In the other study, researchers raised an alarm after finding a high rate of PAD in patients with gout regardless of whether they also had diabetes, which is a known risk factor for PAD. “Our data suggest that gout is an underrecognized risk factor for PAD and indicates the importance of assessing for PAD in gout patients,” lead author Nicole Leung, MD, of NYU Langone Health, said in a presentation.
According to Dr. Leung, there’s little known about links between PAD and gout, although she highlighted a 2018 study that found that patients with obstructive coronary artery disease were more likely to have poor outcomes if they also developed gout after catheterization. She highlighted a 2022 study that found higher rates of lower-extremity amputations in patients with gout independent of cardiovascular disease and diabetes. However, she noted that a link to PAD is unclear, and the study found a link between gout and amputations that was independent of PAD.
Patients with gout, she added, are not routinely screened for PAD.
For the new retrospective, cross-sectional analysis, Dr. Leung and colleagues examined Veterans Administration data from 2014 to 2018 for 7.2 million patients. The population was largely male.
Of those, 140,862 (2.52%) – the control group – had no gout or diabetes. In comparison, 11,449 (5.56%) of 205,904 with gout but not diabetes had PAD, for a rate 2.2 times greater than the control group). PAD occurred in 101,582 (8.70%) of 1,168,138 with diabetes but not gout, giving a rate 3.2 times greater than the control group. The rate was highest among people with both gout and diabetes, at 9.97% (9,905 of 99,377), which is about four times greater than the control group.
The link between gout and PAD remained after adjustment for creatinine levels, age, gender, and body mass index. Diabetes was linked to a higher risk for PAD than was gout, and the effect of both conditions combined was “less than additive.” This “may suggest an overlap and pathophysiology between the two,” she said.
Disclosure information was not provided. The Rheumatology Research Foundation funded the PAD study; funding information for the ULT/gout flare analysis was not provided.
AT G-CAN 2023
AI algorithm aids egg retrieval date during fertility treatment cycles
According to the researchers, such an algorithm is needed due to the increased demand for fertility treatments, as well as the high day-to-day variability in lab workload.
According to the study investigators, predicting retrieval dates in advance for ongoing cycles is of major importance for both patients and clinicians.
“The population requiring fertility treatments, including genetic testing and fertility preservation, has massively increased, and this causes many more cycles and a high day-to-day variability in IVF activity, especially in the lab workload,” said Rohi Hourvitz, MBA, from FertilAI, an Israeli health care company focused on developing technologies that improve fertility treatments.
“We also need to accommodate and reschedule for non-working days, which causes a big issue with managing the workload in many clinics around the world,” added Mr. Hourvitz, who presented the research highlighting AI’s growing role in reproductive medicine.
In addition, AI has recently emerged as an effective tool for assisting in clinical decision-making in assisted reproductive technology, prompting further research in this space, he said.
The new study used a dataset of 9,550 predictable antagonist cycles (defined as having all necessary data) gathered from one lab with over 50 physicians between August 2018 and October 2022. The data were split into two subsets: one for training the AI model and the other for prospective testing.
To train and test the AI model, data from nearly 6,000 predictable antagonist cycles were used. Key factors used for each cycle included estrogen levels, mean follicle size, primary follicle size, and various patient demographics. Other features were considered, but Mr. Hourvitz noted that primary follicle size influenced the algorithm most, “because that is what most of us use when we want to trigger.”
Mr. Hourvitz explained that these patient data were run through an algorithm that produced a graph predicting the most probable date for a cycle retrieval.
“We could accurately predict when those ‘peak days’ were going to be happening in the clinic, and we could also give a pretty good estimate on how many cycles you’re going to have every day,” Mr. Hourvitz said, explaining that this information could help clinics more efficiently allocate resources and manage patients.
According to Mr. Hourvitz, the predictions derived from this study could improve various aspects of fertility treatments and related procedures, including better staff planning and caseload management in IVF labs, as well as higher-quality eggs at retrieval. Patients would have a clearer timeline for their treatment cycles.
Nikica Zaninovic, PhD, MS, director of the embryology lab at Weill Cornell Medical College, New York City, cautioned that the new findings are not yet ready for clinical application but emphasized the importance of more AI research focusing on the quality of oocytes, not only embryos.
“We’re so focused on the end of the process: the embryo,” Dr. Zaninovic, who was not involved in the research, said in an interview. “I think the focus should be on the beginning – the quality of eggs and sperm, not just the quantity – because that’s what the embryos will depend on.”
He noted the increasing numbers of young women in the United States undergoing egg freezing.
“Cornell is the largest academic IVF center in the United States; 20%-30% of all of the patients that we treat are actually freezing their eggs,” he said. “It’s a huge population.”
“When they come to us, they ask how many eggs they’ll need to guarantee one or two children in the future,” Dr. Zaninovic continued. “We don’t have that answer, so we always tell them [we’ll retrieve] as many as we can. That’s not the answer; we need to be more precise. We’re still lacking these tools, and I think that’s where the research will go.”
The study was funded by FertilAI. Mr. Hourvitz is a shareholder and CEO of FertilAI. Dr. Zaninovic is president of the AI Fertility Society.
A version of this article appeared on Medscape.com.
According to the researchers, such an algorithm is needed due to the increased demand for fertility treatments, as well as the high day-to-day variability in lab workload.
According to the study investigators, predicting retrieval dates in advance for ongoing cycles is of major importance for both patients and clinicians.
“The population requiring fertility treatments, including genetic testing and fertility preservation, has massively increased, and this causes many more cycles and a high day-to-day variability in IVF activity, especially in the lab workload,” said Rohi Hourvitz, MBA, from FertilAI, an Israeli health care company focused on developing technologies that improve fertility treatments.
“We also need to accommodate and reschedule for non-working days, which causes a big issue with managing the workload in many clinics around the world,” added Mr. Hourvitz, who presented the research highlighting AI’s growing role in reproductive medicine.
In addition, AI has recently emerged as an effective tool for assisting in clinical decision-making in assisted reproductive technology, prompting further research in this space, he said.
The new study used a dataset of 9,550 predictable antagonist cycles (defined as having all necessary data) gathered from one lab with over 50 physicians between August 2018 and October 2022. The data were split into two subsets: one for training the AI model and the other for prospective testing.
To train and test the AI model, data from nearly 6,000 predictable antagonist cycles were used. Key factors used for each cycle included estrogen levels, mean follicle size, primary follicle size, and various patient demographics. Other features were considered, but Mr. Hourvitz noted that primary follicle size influenced the algorithm most, “because that is what most of us use when we want to trigger.”
Mr. Hourvitz explained that these patient data were run through an algorithm that produced a graph predicting the most probable date for a cycle retrieval.
“We could accurately predict when those ‘peak days’ were going to be happening in the clinic, and we could also give a pretty good estimate on how many cycles you’re going to have every day,” Mr. Hourvitz said, explaining that this information could help clinics more efficiently allocate resources and manage patients.
According to Mr. Hourvitz, the predictions derived from this study could improve various aspects of fertility treatments and related procedures, including better staff planning and caseload management in IVF labs, as well as higher-quality eggs at retrieval. Patients would have a clearer timeline for their treatment cycles.
Nikica Zaninovic, PhD, MS, director of the embryology lab at Weill Cornell Medical College, New York City, cautioned that the new findings are not yet ready for clinical application but emphasized the importance of more AI research focusing on the quality of oocytes, not only embryos.
“We’re so focused on the end of the process: the embryo,” Dr. Zaninovic, who was not involved in the research, said in an interview. “I think the focus should be on the beginning – the quality of eggs and sperm, not just the quantity – because that’s what the embryos will depend on.”
He noted the increasing numbers of young women in the United States undergoing egg freezing.
“Cornell is the largest academic IVF center in the United States; 20%-30% of all of the patients that we treat are actually freezing their eggs,” he said. “It’s a huge population.”
“When they come to us, they ask how many eggs they’ll need to guarantee one or two children in the future,” Dr. Zaninovic continued. “We don’t have that answer, so we always tell them [we’ll retrieve] as many as we can. That’s not the answer; we need to be more precise. We’re still lacking these tools, and I think that’s where the research will go.”
The study was funded by FertilAI. Mr. Hourvitz is a shareholder and CEO of FertilAI. Dr. Zaninovic is president of the AI Fertility Society.
A version of this article appeared on Medscape.com.
According to the researchers, such an algorithm is needed due to the increased demand for fertility treatments, as well as the high day-to-day variability in lab workload.
According to the study investigators, predicting retrieval dates in advance for ongoing cycles is of major importance for both patients and clinicians.
“The population requiring fertility treatments, including genetic testing and fertility preservation, has massively increased, and this causes many more cycles and a high day-to-day variability in IVF activity, especially in the lab workload,” said Rohi Hourvitz, MBA, from FertilAI, an Israeli health care company focused on developing technologies that improve fertility treatments.
“We also need to accommodate and reschedule for non-working days, which causes a big issue with managing the workload in many clinics around the world,” added Mr. Hourvitz, who presented the research highlighting AI’s growing role in reproductive medicine.
In addition, AI has recently emerged as an effective tool for assisting in clinical decision-making in assisted reproductive technology, prompting further research in this space, he said.
The new study used a dataset of 9,550 predictable antagonist cycles (defined as having all necessary data) gathered from one lab with over 50 physicians between August 2018 and October 2022. The data were split into two subsets: one for training the AI model and the other for prospective testing.
To train and test the AI model, data from nearly 6,000 predictable antagonist cycles were used. Key factors used for each cycle included estrogen levels, mean follicle size, primary follicle size, and various patient demographics. Other features were considered, but Mr. Hourvitz noted that primary follicle size influenced the algorithm most, “because that is what most of us use when we want to trigger.”
Mr. Hourvitz explained that these patient data were run through an algorithm that produced a graph predicting the most probable date for a cycle retrieval.
“We could accurately predict when those ‘peak days’ were going to be happening in the clinic, and we could also give a pretty good estimate on how many cycles you’re going to have every day,” Mr. Hourvitz said, explaining that this information could help clinics more efficiently allocate resources and manage patients.
According to Mr. Hourvitz, the predictions derived from this study could improve various aspects of fertility treatments and related procedures, including better staff planning and caseload management in IVF labs, as well as higher-quality eggs at retrieval. Patients would have a clearer timeline for their treatment cycles.
Nikica Zaninovic, PhD, MS, director of the embryology lab at Weill Cornell Medical College, New York City, cautioned that the new findings are not yet ready for clinical application but emphasized the importance of more AI research focusing on the quality of oocytes, not only embryos.
“We’re so focused on the end of the process: the embryo,” Dr. Zaninovic, who was not involved in the research, said in an interview. “I think the focus should be on the beginning – the quality of eggs and sperm, not just the quantity – because that’s what the embryos will depend on.”
He noted the increasing numbers of young women in the United States undergoing egg freezing.
“Cornell is the largest academic IVF center in the United States; 20%-30% of all of the patients that we treat are actually freezing their eggs,” he said. “It’s a huge population.”
“When they come to us, they ask how many eggs they’ll need to guarantee one or two children in the future,” Dr. Zaninovic continued. “We don’t have that answer, so we always tell them [we’ll retrieve] as many as we can. That’s not the answer; we need to be more precise. We’re still lacking these tools, and I think that’s where the research will go.”
The study was funded by FertilAI. Mr. Hourvitz is a shareholder and CEO of FertilAI. Dr. Zaninovic is president of the AI Fertility Society.
A version of this article appeared on Medscape.com.
FROM ASRM 2023