Conference Coverage

SAN DIEGO –After fashion model Linda Evangelista filed and ultimately settled a lawsuit against Zeltiq Aesthetics in 2022 subsequent to developing paradoxical adipose hyperplasia she claimed was caused by several sessions of CoolSculpting, some aesthetic experts wondered how consumers would embrace the fat reduction procedure going forward.

The negative publicity surrounding this case “is thought to have detracted from some of the volume of it [in terms of demand], but it looks like it’s coming back again,” Omar A. Ibrahimi, MD, PhD, medical director of the Connecticut Skin Institute, Stamford, said during a presentation on noninvasive fat removal treatment options at the annual Masters of Aesthetics Symposium.

In fact, he said, CoolSculpting accounts for an estimated 72% of noninvasive fat removal treatments performed in the United States. “By and large, there is high satisfaction with this procedure,” said Dr. Ibrahimi. “There have been about 17 million procedures done worldwide. Paradoxical adipose hyperplasia is a very rare side effect. As newer iterations of this technology have come out, I think there is an even lower incidence.”

CoolSculpting, or cryolipolysis, freezes excess fat to remove it from stubborn areas via panniculitis. The technology was developed by Dieter Manstein MD, PhD, and R. Rox Anderson, MD, at Massachusetts General Hospital and Harvard Medical School, both in Boston, and cleared by the U.S. Food and Drug Administration for noninvasive fat removal in 2010.

“If you kill a fat cell in an adult, it can’t come back,” Dr. Ibrahimi said. “When this technology first came out it was very simple. We treated an area once and were done. Now we know to treat the area multiple times, and you can treat a much larger volume in a patient during one session safely. You can bring about dramatic results, but it often takes a series of 35-minute treatment cycles and about 3 months to see clinical results. There are published studies showing that results are persisting even 10 years after treatment. This is nice, because I tell my patients, ‘if you keep up with your diet and exercise, we don’t expect the fat to come back.’ ”

Other noninvasive options for fat removal include the following:

• Ultrasound. Options include high-intensity focused ultrasound (Liposonix) and pulsed focused ultrasound (UltraShape). Dr. Ibrahimi described these devices as “very painful, and the results were very difficult to reproduce from the initial clinical studies.”
• Low-level light therapy. Early devices on the market include Zerona and UltraSlim. “Oftentimes these lacked any sort of histological analysis,” he said. “There was no obvious mechanism of action, and questionable efficacy.”
• Laser. Powered by a 1060-nm laser, SculpSure can reduce fat cells safely in 25-minute treatment sessions, Dr. Ibrahimi said. Each session is delivered with one of four available applicators and involves 4 minutes of heating and the next 21 minutes alternating between heating and cooling. “You’re trying to reach a target temperature that kills fat cells,” he explained. “The beauty of having these applicators is that you can kind of customize to the individual patient; it uses contact cooling, and it’s safe for all Fitzpatrick skin types. This device results in a 10%-12% reduction in fat, so it’s clinically significant but very modest.”

A robotic version of the technology, known as the Robotic Fat Killer, is also available. So is the EON, a touchless 1064-nm laser FDA cleared for abdominal, flank, thigh, and back fat reduction. “It adapts to the body shape of the area and individual to deliver a customized treatment,” Dr. Ibrahimi said.

• Radiofrequency. Most devices on the market, such as truSculpt and Vanquish, are powered by monopolar radiofrequency (RF) energy. “Similar to the 1060-nm laser, you can customize these treatments,” he said. “You’re treating to a target temperature. It involves 15-minute cycles, and there are clinical, histology, and ultrasound data supporting this technology.”

Dr. Ibrahimi uses truSculpt and CoolSculpting in his practice, “but sometimes you have patients who are ‘too fit’ for CoolSculpting; they don’t fit the handpiece perfectly,” he said. “That’s where having a monopolar RF or a 1060-nm laser is useful, to help you hone in on those stubborn pockets of fat.”

• Deoxycholic acid. While not a device, deoxycholic acid (Kybella), administered subcutaneously, is approved by the FDA for improving “the appearance of moderate to severe convexity or fullness associated with submental fat” in adults. “A lot of people use it off-label on the abdomen and other stubborn areas,” Dr. Ibrahimi said. “It often requires a series of treatments. That’s the biggest limiting issue with using this technology. It works well, but compared to CoolSculpting, there is a lot of swelling and bruising, which you would expect with an injectable. Managing that down time and hand holding is difficult. But if you can get patients to buy into the downtime, [it yields] pretty impressive results.”

Dr. Ibrahimi also discussed the promise of electrical muscle stimulation for strengthening, firming, and toning muscles. The technology applies an electrical current through electrodes placed on the skin, which stimulates muscles, or through an electromagnetic field.

In a published study of 45 men and women, Dr. Ibrahimi, Anne Chapas, MD, medical director of UnionDerm in New York, and colleagues evaluated the safety and efficacy of an electrical muscle stimulation system for improving muscle strength and toning of the upper extremities.

For the treatments, they used disposable contact pads to place pairs of electrodes on the biceps and on the triceps. All patients (median age 42) received 30-minute treatments twice weekly for 2 or 3 weeks, corresponding to four or six total sessions respectively, depending on the study site. Follow-ups were conducted 30 and 90 days after treatment. They used a validated dynamometer device to measure strength at baseline, at the final treatment session, and at the post-treatment 30- and 90-day visits.

“We saw about a 40% increase in strength in the biceps and about a 30% increase in strength in the triceps,” Dr. Ibrahimi said. “Interestingly, the effect got greater at 30 and 90 days, so this is something that lingers on for quite a while.” In addition to the increase in strength, the researchers and patients noted an improvement in the appearance of the arms. He predicted that this technology “is going to play a role in functional medicine and getting injured athletes back to their sports faster.”

Dr. Ibrahimi disclosed that he is a member of the Advisory Board for Accure Acne, AbbVie, Cutera (manufacturer of truSculpt), Lutronic, Blueberry Therapeutics, Cytrellis, and Quthero. He also holds stock in many device and pharmaceutical companies (none are relevant to the treatments mentioned in this story).

SAN DIEGO –After fashion model Linda Evangelista filed and ultimately settled a lawsuit against Zeltiq Aesthetics in 2022 subsequent to developing paradoxical adipose hyperplasia she claimed was caused by several sessions of CoolSculpting, some aesthetic experts wondered how consumers would embrace the fat reduction procedure going forward.

The negative publicity surrounding this case “is thought to have detracted from some of the volume of it [in terms of demand], but it looks like it’s coming back again,” Omar A. Ibrahimi, MD, PhD, medical director of the Connecticut Skin Institute, Stamford, said during a presentation on noninvasive fat removal treatment options at the annual Masters of Aesthetics Symposium.

In fact, he said, CoolSculpting accounts for an estimated 72% of noninvasive fat removal treatments performed in the United States. “By and large, there is high satisfaction with this procedure,” said Dr. Ibrahimi. “There have been about 17 million procedures done worldwide. Paradoxical adipose hyperplasia is a very rare side effect. As newer iterations of this technology have come out, I think there is an even lower incidence.”

CoolSculpting, or cryolipolysis, freezes excess fat to remove it from stubborn areas via panniculitis. The technology was developed by Dieter Manstein MD, PhD, and R. Rox Anderson, MD, at Massachusetts General Hospital and Harvard Medical School, both in Boston, and cleared by the U.S. Food and Drug Administration for noninvasive fat removal in 2010.

“If you kill a fat cell in an adult, it can’t come back,” Dr. Ibrahimi said. “When this technology first came out it was very simple. We treated an area once and were done. Now we know to treat the area multiple times, and you can treat a much larger volume in a patient during one session safely. You can bring about dramatic results, but it often takes a series of 35-minute treatment cycles and about 3 months to see clinical results. There are published studies showing that results are persisting even 10 years after treatment. This is nice, because I tell my patients, ‘if you keep up with your diet and exercise, we don’t expect the fat to come back.’ ”

Other noninvasive options for fat removal include the following:

• Ultrasound. Options include high-intensity focused ultrasound (Liposonix) and pulsed focused ultrasound (UltraShape). Dr. Ibrahimi described these devices as “very painful, and the results were very difficult to reproduce from the initial clinical studies.”
• Low-level light therapy. Early devices on the market include Zerona and UltraSlim. “Oftentimes these lacked any sort of histological analysis,” he said. “There was no obvious mechanism of action, and questionable efficacy.”
• Laser. Powered by a 1060-nm laser, SculpSure can reduce fat cells safely in 25-minute treatment sessions, Dr. Ibrahimi said. Each session is delivered with one of four available applicators and involves 4 minutes of heating and the next 21 minutes alternating between heating and cooling. “You’re trying to reach a target temperature that kills fat cells,” he explained. “The beauty of having these applicators is that you can kind of customize to the individual patient; it uses contact cooling, and it’s safe for all Fitzpatrick skin types. This device results in a 10%-12% reduction in fat, so it’s clinically significant but very modest.”

A robotic version of the technology, known as the Robotic Fat Killer, is also available. So is the EON, a touchless 1064-nm laser FDA cleared for abdominal, flank, thigh, and back fat reduction. “It adapts to the body shape of the area and individual to deliver a customized treatment,” Dr. Ibrahimi said.

• Radiofrequency. Most devices on the market, such as truSculpt and Vanquish, are powered by monopolar radiofrequency (RF) energy. “Similar to the 1060-nm laser, you can customize these treatments,” he said. “You’re treating to a target temperature. It involves 15-minute cycles, and there are clinical, histology, and ultrasound data supporting this technology.”

Dr. Ibrahimi uses truSculpt and CoolSculpting in his practice, “but sometimes you have patients who are ‘too fit’ for CoolSculpting; they don’t fit the handpiece perfectly,” he said. “That’s where having a monopolar RF or a 1060-nm laser is useful, to help you hone in on those stubborn pockets of fat.”

• Deoxycholic acid. While not a device, deoxycholic acid (Kybella), administered subcutaneously, is approved by the FDA for improving “the appearance of moderate to severe convexity or fullness associated with submental fat” in adults. “A lot of people use it off-label on the abdomen and other stubborn areas,” Dr. Ibrahimi said. “It often requires a series of treatments. That’s the biggest limiting issue with using this technology. It works well, but compared to CoolSculpting, there is a lot of swelling and bruising, which you would expect with an injectable. Managing that down time and hand holding is difficult. But if you can get patients to buy into the downtime, [it yields] pretty impressive results.”

Dr. Ibrahimi also discussed the promise of electrical muscle stimulation for strengthening, firming, and toning muscles. The technology applies an electrical current through electrodes placed on the skin, which stimulates muscles, or through an electromagnetic field.

In a published study of 45 men and women, Dr. Ibrahimi, Anne Chapas, MD, medical director of UnionDerm in New York, and colleagues evaluated the safety and efficacy of an electrical muscle stimulation system for improving muscle strength and toning of the upper extremities.

For the treatments, they used disposable contact pads to place pairs of electrodes on the biceps and on the triceps. All patients (median age 42) received 30-minute treatments twice weekly for 2 or 3 weeks, corresponding to four or six total sessions respectively, depending on the study site. Follow-ups were conducted 30 and 90 days after treatment. They used a validated dynamometer device to measure strength at baseline, at the final treatment session, and at the post-treatment 30- and 90-day visits.

“We saw about a 40% increase in strength in the biceps and about a 30% increase in strength in the triceps,” Dr. Ibrahimi said. “Interestingly, the effect got greater at 30 and 90 days, so this is something that lingers on for quite a while.” In addition to the increase in strength, the researchers and patients noted an improvement in the appearance of the arms. He predicted that this technology “is going to play a role in functional medicine and getting injured athletes back to their sports faster.”

Dr. Ibrahimi disclosed that he is a member of the Advisory Board for Accure Acne, AbbVie, Cutera (manufacturer of truSculpt), Lutronic, Blueberry Therapeutics, Cytrellis, and Quthero. He also holds stock in many device and pharmaceutical companies (none are relevant to the treatments mentioned in this story).

SAN DIEGO –After fashion model Linda Evangelista filed and ultimately settled a lawsuit against Zeltiq Aesthetics in 2022 subsequent to developing paradoxical adipose hyperplasia she claimed was caused by several sessions of CoolSculpting, some aesthetic experts wondered how consumers would embrace the fat reduction procedure going forward.

The negative publicity surrounding this case “is thought to have detracted from some of the volume of it [in terms of demand], but it looks like it’s coming back again,” Omar A. Ibrahimi, MD, PhD, medical director of the Connecticut Skin Institute, Stamford, said during a presentation on noninvasive fat removal treatment options at the annual Masters of Aesthetics Symposium.

In fact, he said, CoolSculpting accounts for an estimated 72% of noninvasive fat removal treatments performed in the United States. “By and large, there is high satisfaction with this procedure,” said Dr. Ibrahimi. “There have been about 17 million procedures done worldwide. Paradoxical adipose hyperplasia is a very rare side effect. As newer iterations of this technology have come out, I think there is an even lower incidence.”

CoolSculpting, or cryolipolysis, freezes excess fat to remove it from stubborn areas via panniculitis. The technology was developed by Dieter Manstein MD, PhD, and R. Rox Anderson, MD, at Massachusetts General Hospital and Harvard Medical School, both in Boston, and cleared by the U.S. Food and Drug Administration for noninvasive fat removal in 2010.

“If you kill a fat cell in an adult, it can’t come back,” Dr. Ibrahimi said. “When this technology first came out it was very simple. We treated an area once and were done. Now we know to treat the area multiple times, and you can treat a much larger volume in a patient during one session safely. You can bring about dramatic results, but it often takes a series of 35-minute treatment cycles and about 3 months to see clinical results. There are published studies showing that results are persisting even 10 years after treatment. This is nice, because I tell my patients, ‘if you keep up with your diet and exercise, we don’t expect the fat to come back.’ ”

Other noninvasive options for fat removal include the following:

• Ultrasound. Options include high-intensity focused ultrasound (Liposonix) and pulsed focused ultrasound (UltraShape). Dr. Ibrahimi described these devices as “very painful, and the results were very difficult to reproduce from the initial clinical studies.”
• Low-level light therapy. Early devices on the market include Zerona and UltraSlim. “Oftentimes these lacked any sort of histological analysis,” he said. “There was no obvious mechanism of action, and questionable efficacy.”
• Laser. Powered by a 1060-nm laser, SculpSure can reduce fat cells safely in 25-minute treatment sessions, Dr. Ibrahimi said. Each session is delivered with one of four available applicators and involves 4 minutes of heating and the next 21 minutes alternating between heating and cooling. “You’re trying to reach a target temperature that kills fat cells,” he explained. “The beauty of having these applicators is that you can kind of customize to the individual patient; it uses contact cooling, and it’s safe for all Fitzpatrick skin types. This device results in a 10%-12% reduction in fat, so it’s clinically significant but very modest.”

A robotic version of the technology, known as the Robotic Fat Killer, is also available. So is the EON, a touchless 1064-nm laser FDA cleared for abdominal, flank, thigh, and back fat reduction. “It adapts to the body shape of the area and individual to deliver a customized treatment,” Dr. Ibrahimi said.

• Radiofrequency. Most devices on the market, such as truSculpt and Vanquish, are powered by monopolar radiofrequency (RF) energy. “Similar to the 1060-nm laser, you can customize these treatments,” he said. “You’re treating to a target temperature. It involves 15-minute cycles, and there are clinical, histology, and ultrasound data supporting this technology.”

Dr. Ibrahimi uses truSculpt and CoolSculpting in his practice, “but sometimes you have patients who are ‘too fit’ for CoolSculpting; they don’t fit the handpiece perfectly,” he said. “That’s where having a monopolar RF or a 1060-nm laser is useful, to help you hone in on those stubborn pockets of fat.”

• Deoxycholic acid. While not a device, deoxycholic acid (Kybella), administered subcutaneously, is approved by the FDA for improving “the appearance of moderate to severe convexity or fullness associated with submental fat” in adults. “A lot of people use it off-label on the abdomen and other stubborn areas,” Dr. Ibrahimi said. “It often requires a series of treatments. That’s the biggest limiting issue with using this technology. It works well, but compared to CoolSculpting, there is a lot of swelling and bruising, which you would expect with an injectable. Managing that down time and hand holding is difficult. But if you can get patients to buy into the downtime, [it yields] pretty impressive results.”

Dr. Ibrahimi also discussed the promise of electrical muscle stimulation for strengthening, firming, and toning muscles. The technology applies an electrical current through electrodes placed on the skin, which stimulates muscles, or through an electromagnetic field.

In a published study of 45 men and women, Dr. Ibrahimi, Anne Chapas, MD, medical director of UnionDerm in New York, and colleagues evaluated the safety and efficacy of an electrical muscle stimulation system for improving muscle strength and toning of the upper extremities.

For the treatments, they used disposable contact pads to place pairs of electrodes on the biceps and on the triceps. All patients (median age 42) received 30-minute treatments twice weekly for 2 or 3 weeks, corresponding to four or six total sessions respectively, depending on the study site. Follow-ups were conducted 30 and 90 days after treatment. They used a validated dynamometer device to measure strength at baseline, at the final treatment session, and at the post-treatment 30- and 90-day visits.

“We saw about a 40% increase in strength in the biceps and about a 30% increase in strength in the triceps,” Dr. Ibrahimi said. “Interestingly, the effect got greater at 30 and 90 days, so this is something that lingers on for quite a while.” In addition to the increase in strength, the researchers and patients noted an improvement in the appearance of the arms. He predicted that this technology “is going to play a role in functional medicine and getting injured athletes back to their sports faster.”

Dr. Ibrahimi disclosed that he is a member of the Advisory Board for Accure Acne, AbbVie, Cutera (manufacturer of truSculpt), Lutronic, Blueberry Therapeutics, Cytrellis, and Quthero. He also holds stock in many device and pharmaceutical companies (none are relevant to the treatments mentioned in this story).

AMSTERDAM – Dropping aspirin and using low-dose prasugrel (Effient) alone in the initial month of treatment after percutaneous coronary intervention (PCI) failed to lower bleeding risk, compared with dual antiplatelet therapy (DAPT), and there was a signal of possible harm in terms of increased subacute stent thrombosis, in the STOPDAPT-3 trial.

“Therefore, dual antiplatelet therapy with aspirin and a P2Y12 inhibitor should still remain the standard strategy at least for 1 month after PCI,” said the trial’s lead investigator Masahiro Natsuaki, MD, Saga (Japan) University.

The STOPDAPT-3 trial was presented at the recent annual congress of the European Society of Cardiology.

Designated discussant Marco Valgimigli, MD, Cardiocentro Ticino Foundation, Lugano, Switzerland, explained that the current wisdom before this study was that aspirin withdrawal in the postacute phase after PCI (after 1 month of DAPT onwards) is associated with lower bleeding risk without affecting ischemic risk, but this STOPDAPT-3 trial is the first to look at the idea of not giving aspirin at all.

“This study is a well-designed, well-conducted trial, and the results are very clear: there is no benefit of dropping aspirin in this early period with respect to major bleeding, and at the same time there was some signal for possible harm,” Dr. Valgimigli said.

He pointed out that the possible harm was not related to the coprimary cardiovascular composite endpoint, which did fulfill noninferiority, although he acknowledged the “generous” noninferiority margin.

Rather, the possible harm was related to an increase in subacute stent thrombosis, which was three times higher in the nonaspirin group (0.58% vs. 0.17%). 

“While these absolute event rates are extremely low, they are unquestionably higher in the nonaspirin group,” he added.

In his presentation, Dr. Natsuaki explained that very short durations (1-3 months) of DAPT followed by P2Y12 inhibitor monotherapy has been shown to reduce bleeding events without increasing cardiovascular events, compared with longer durations of DAPT after PCI using drug-eluting stents.

However, the incidence of major bleeding events within the 1-month mandatory DAPT period after PCI remains high in clinical practice, particularly in patients with ACS or high bleeding risk.

In single-arm studies, use of prasugrel or ticagrelor (Brilinta) alone following new-generation drug-eluting stent implantation was not associated with any stent thrombosis in selected low-risk patients with or without ACS, and it is thought that removing aspirin from the DAPT regimen might reduce bleeding events early after PCI without compromising the risk of cardiovascular events. However, the efficacy and safety of this strategy has not been proven in randomized trials.
 

STOPDAPT-3 trial

STOPDAPT-3 investigated the efficacy and safety of prasugrel monotherapy compared with 1-month DAPT with aspirin and prasugrel in Japanese patients with ACS or high bleeding risk undergoing PCI with cobalt-chromium everolimus-eluting stents.

The study enrolled 6,002 patients with ACS or high bleeding risk who were randomly assigned to prasugrel monotherapy (3.75 mg/day; the licensed dose in Japan) or to DAPT with aspirin (81-100 mg/day) and prasugrel after a loading dose of prasugrel 20 mg in both groups.

There were two primary endpoints: major bleeding events (defined as BARC type 3 or 5) at 1 month for superiority and cardiovascular events (a composite of cardiovascular death, myocardial infarction, definite stent thrombosis, or stroke) at 1 month for noninferiority.

The major secondary endpoint was a composite of the coprimary bleeding and cardiovascular endpoints (cardiovascular death, myocardial infarction, definite stent thrombosis, stroke, or major bleeding) at 1 month representing net clinical benefit.

Results showed that, at 1 month, the no-aspirin strategy was not superior to DAPT for the coprimary bleeding endpoint, with major bleeding events occurring in 4.47% of the prasugrel monotherapy group versus 4.71% of those on DAPT (hazard ratio, 0.95; 95% confidence interval, 0.75-1.20).

The prasugrel monotherapy strategy was noninferior to DAPT, although there was a relative 50% margin for the coprimary cardiovascular endpoint. Cardiovascular endpoints occurred in 4.12% of prasugrel monotherapy group versus 3.69% of the DAPT patients (HR, 1.12; 95% CI, 0.87-1.45; P for noninferiority = .01).

The major secondary net clinical benefit endpoint occurred in 7.14% patients in the prasugrel monotherapy group and 7.38% patients in the DAPT group, with no between-group difference, indicating a similar effect on net clinical benefit for both groups.

However, there was an excess of any coronary revascularization (1.15% vs. 0.57%) and definite or probable stent thrombosis (0.71% vs. 0.44%) in the prasugrel monotherapy group compared with the DAPT group, while definite stent thrombosis was not different between the two groups (0.47% vs. 0.37%).

In a subgroup analysis stratified by ACS and non-ACS, the excess risk for cardiovascular events in the no-aspirin group, compared with the DAPT group, was seen in patients with ACS, but not in those without ACS.
 

Future: Focus on dose and timing

In his discussion, Dr. Valgimigli said the implications of this trial for clinical practice were very clear: “Aspirin remains a cornerstone treatment in the periprocedural and acute phase of PCI in patients without indications for oral anticoagulation.” 

However, he added that the study opens several important points for subsequent discussion.

These include the role of type and dose of P2Y12 inhibitor therapy used; specifically, he questioned whether the 3.75-mg dose of prasugrel was enough.

Dr. Valgimigli also pointed out that this study did not include a purely high bleeding risk population, and he said there was still potential to investigate periprocedure versus postprocedure aspirin administration.

The STOPDAPT-3 trial was funded by Abbott Medical Japan. Dr. Natsuaki reported receiving honoraria from Abbott Medical Japan, Daiichi Sankyo, and Bayer.

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

AMSTERDAM – Dropping aspirin and using low-dose prasugrel (Effient) alone in the initial month of treatment after percutaneous coronary intervention (PCI) failed to lower bleeding risk, compared with dual antiplatelet therapy (DAPT), and there was a signal of possible harm in terms of increased subacute stent thrombosis, in the STOPDAPT-3 trial.

“Therefore, dual antiplatelet therapy with aspirin and a P2Y12 inhibitor should still remain the standard strategy at least for 1 month after PCI,” said the trial’s lead investigator Masahiro Natsuaki, MD, Saga (Japan) University.

The STOPDAPT-3 trial was presented at the recent annual congress of the European Society of Cardiology.

Designated discussant Marco Valgimigli, MD, Cardiocentro Ticino Foundation, Lugano, Switzerland, explained that the current wisdom before this study was that aspirin withdrawal in the postacute phase after PCI (after 1 month of DAPT onwards) is associated with lower bleeding risk without affecting ischemic risk, but this STOPDAPT-3 trial is the first to look at the idea of not giving aspirin at all.

“This study is a well-designed, well-conducted trial, and the results are very clear: there is no benefit of dropping aspirin in this early period with respect to major bleeding, and at the same time there was some signal for possible harm,” Dr. Valgimigli said.

He pointed out that the possible harm was not related to the coprimary cardiovascular composite endpoint, which did fulfill noninferiority, although he acknowledged the “generous” noninferiority margin.

Rather, the possible harm was related to an increase in subacute stent thrombosis, which was three times higher in the nonaspirin group (0.58% vs. 0.17%). 

“While these absolute event rates are extremely low, they are unquestionably higher in the nonaspirin group,” he added.

In his presentation, Dr. Natsuaki explained that very short durations (1-3 months) of DAPT followed by P2Y12 inhibitor monotherapy has been shown to reduce bleeding events without increasing cardiovascular events, compared with longer durations of DAPT after PCI using drug-eluting stents.

However, the incidence of major bleeding events within the 1-month mandatory DAPT period after PCI remains high in clinical practice, particularly in patients with ACS or high bleeding risk.

In single-arm studies, use of prasugrel or ticagrelor (Brilinta) alone following new-generation drug-eluting stent implantation was not associated with any stent thrombosis in selected low-risk patients with or without ACS, and it is thought that removing aspirin from the DAPT regimen might reduce bleeding events early after PCI without compromising the risk of cardiovascular events. However, the efficacy and safety of this strategy has not been proven in randomized trials.
 

STOPDAPT-3 trial

STOPDAPT-3 investigated the efficacy and safety of prasugrel monotherapy compared with 1-month DAPT with aspirin and prasugrel in Japanese patients with ACS or high bleeding risk undergoing PCI with cobalt-chromium everolimus-eluting stents.

The study enrolled 6,002 patients with ACS or high bleeding risk who were randomly assigned to prasugrel monotherapy (3.75 mg/day; the licensed dose in Japan) or to DAPT with aspirin (81-100 mg/day) and prasugrel after a loading dose of prasugrel 20 mg in both groups.

There were two primary endpoints: major bleeding events (defined as BARC type 3 or 5) at 1 month for superiority and cardiovascular events (a composite of cardiovascular death, myocardial infarction, definite stent thrombosis, or stroke) at 1 month for noninferiority.

The major secondary endpoint was a composite of the coprimary bleeding and cardiovascular endpoints (cardiovascular death, myocardial infarction, definite stent thrombosis, stroke, or major bleeding) at 1 month representing net clinical benefit.

Results showed that, at 1 month, the no-aspirin strategy was not superior to DAPT for the coprimary bleeding endpoint, with major bleeding events occurring in 4.47% of the prasugrel monotherapy group versus 4.71% of those on DAPT (hazard ratio, 0.95; 95% confidence interval, 0.75-1.20).

The prasugrel monotherapy strategy was noninferior to DAPT, although there was a relative 50% margin for the coprimary cardiovascular endpoint. Cardiovascular endpoints occurred in 4.12% of prasugrel monotherapy group versus 3.69% of the DAPT patients (HR, 1.12; 95% CI, 0.87-1.45; P for noninferiority = .01).

The major secondary net clinical benefit endpoint occurred in 7.14% patients in the prasugrel monotherapy group and 7.38% patients in the DAPT group, with no between-group difference, indicating a similar effect on net clinical benefit for both groups.

However, there was an excess of any coronary revascularization (1.15% vs. 0.57%) and definite or probable stent thrombosis (0.71% vs. 0.44%) in the prasugrel monotherapy group compared with the DAPT group, while definite stent thrombosis was not different between the two groups (0.47% vs. 0.37%).

In a subgroup analysis stratified by ACS and non-ACS, the excess risk for cardiovascular events in the no-aspirin group, compared with the DAPT group, was seen in patients with ACS, but not in those without ACS.
 

Future: Focus on dose and timing

In his discussion, Dr. Valgimigli said the implications of this trial for clinical practice were very clear: “Aspirin remains a cornerstone treatment in the periprocedural and acute phase of PCI in patients without indications for oral anticoagulation.” 

However, he added that the study opens several important points for subsequent discussion.

These include the role of type and dose of P2Y12 inhibitor therapy used; specifically, he questioned whether the 3.75-mg dose of prasugrel was enough.

Dr. Valgimigli also pointed out that this study did not include a purely high bleeding risk population, and he said there was still potential to investigate periprocedure versus postprocedure aspirin administration.

The STOPDAPT-3 trial was funded by Abbott Medical Japan. Dr. Natsuaki reported receiving honoraria from Abbott Medical Japan, Daiichi Sankyo, and Bayer.

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

AMSTERDAM – Dropping aspirin and using low-dose prasugrel (Effient) alone in the initial month of treatment after percutaneous coronary intervention (PCI) failed to lower bleeding risk, compared with dual antiplatelet therapy (DAPT), and there was a signal of possible harm in terms of increased subacute stent thrombosis, in the STOPDAPT-3 trial.

“Therefore, dual antiplatelet therapy with aspirin and a P2Y12 inhibitor should still remain the standard strategy at least for 1 month after PCI,” said the trial’s lead investigator Masahiro Natsuaki, MD, Saga (Japan) University.

The STOPDAPT-3 trial was presented at the recent annual congress of the European Society of Cardiology.

Designated discussant Marco Valgimigli, MD, Cardiocentro Ticino Foundation, Lugano, Switzerland, explained that the current wisdom before this study was that aspirin withdrawal in the postacute phase after PCI (after 1 month of DAPT onwards) is associated with lower bleeding risk without affecting ischemic risk, but this STOPDAPT-3 trial is the first to look at the idea of not giving aspirin at all.

“This study is a well-designed, well-conducted trial, and the results are very clear: there is no benefit of dropping aspirin in this early period with respect to major bleeding, and at the same time there was some signal for possible harm,” Dr. Valgimigli said.

He pointed out that the possible harm was not related to the coprimary cardiovascular composite endpoint, which did fulfill noninferiority, although he acknowledged the “generous” noninferiority margin.

Rather, the possible harm was related to an increase in subacute stent thrombosis, which was three times higher in the nonaspirin group (0.58% vs. 0.17%). 

“While these absolute event rates are extremely low, they are unquestionably higher in the nonaspirin group,” he added.

In his presentation, Dr. Natsuaki explained that very short durations (1-3 months) of DAPT followed by P2Y12 inhibitor monotherapy has been shown to reduce bleeding events without increasing cardiovascular events, compared with longer durations of DAPT after PCI using drug-eluting stents.

However, the incidence of major bleeding events within the 1-month mandatory DAPT period after PCI remains high in clinical practice, particularly in patients with ACS or high bleeding risk.

In single-arm studies, use of prasugrel or ticagrelor (Brilinta) alone following new-generation drug-eluting stent implantation was not associated with any stent thrombosis in selected low-risk patients with or without ACS, and it is thought that removing aspirin from the DAPT regimen might reduce bleeding events early after PCI without compromising the risk of cardiovascular events. However, the efficacy and safety of this strategy has not been proven in randomized trials.
 

STOPDAPT-3 trial

STOPDAPT-3 investigated the efficacy and safety of prasugrel monotherapy compared with 1-month DAPT with aspirin and prasugrel in Japanese patients with ACS or high bleeding risk undergoing PCI with cobalt-chromium everolimus-eluting stents.

The study enrolled 6,002 patients with ACS or high bleeding risk who were randomly assigned to prasugrel monotherapy (3.75 mg/day; the licensed dose in Japan) or to DAPT with aspirin (81-100 mg/day) and prasugrel after a loading dose of prasugrel 20 mg in both groups.

There were two primary endpoints: major bleeding events (defined as BARC type 3 or 5) at 1 month for superiority and cardiovascular events (a composite of cardiovascular death, myocardial infarction, definite stent thrombosis, or stroke) at 1 month for noninferiority.

The major secondary endpoint was a composite of the coprimary bleeding and cardiovascular endpoints (cardiovascular death, myocardial infarction, definite stent thrombosis, stroke, or major bleeding) at 1 month representing net clinical benefit.

Results showed that, at 1 month, the no-aspirin strategy was not superior to DAPT for the coprimary bleeding endpoint, with major bleeding events occurring in 4.47% of the prasugrel monotherapy group versus 4.71% of those on DAPT (hazard ratio, 0.95; 95% confidence interval, 0.75-1.20).

The prasugrel monotherapy strategy was noninferior to DAPT, although there was a relative 50% margin for the coprimary cardiovascular endpoint. Cardiovascular endpoints occurred in 4.12% of prasugrel monotherapy group versus 3.69% of the DAPT patients (HR, 1.12; 95% CI, 0.87-1.45; P for noninferiority = .01).

The major secondary net clinical benefit endpoint occurred in 7.14% patients in the prasugrel monotherapy group and 7.38% patients in the DAPT group, with no between-group difference, indicating a similar effect on net clinical benefit for both groups.

However, there was an excess of any coronary revascularization (1.15% vs. 0.57%) and definite or probable stent thrombosis (0.71% vs. 0.44%) in the prasugrel monotherapy group compared with the DAPT group, while definite stent thrombosis was not different between the two groups (0.47% vs. 0.37%).

In a subgroup analysis stratified by ACS and non-ACS, the excess risk for cardiovascular events in the no-aspirin group, compared with the DAPT group, was seen in patients with ACS, but not in those without ACS.
 

Future: Focus on dose and timing

In his discussion, Dr. Valgimigli said the implications of this trial for clinical practice were very clear: “Aspirin remains a cornerstone treatment in the periprocedural and acute phase of PCI in patients without indications for oral anticoagulation.” 

However, he added that the study opens several important points for subsequent discussion.

These include the role of type and dose of P2Y12 inhibitor therapy used; specifically, he questioned whether the 3.75-mg dose of prasugrel was enough.

Dr. Valgimigli also pointed out that this study did not include a purely high bleeding risk population, and he said there was still potential to investigate periprocedure versus postprocedure aspirin administration.

The STOPDAPT-3 trial was funded by Abbott Medical Japan. Dr. Natsuaki reported receiving honoraria from Abbott Medical Japan, Daiichi Sankyo, and Bayer.

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

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

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

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

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

Guidelines organize cardiomyopathy phenotypes

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

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

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

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

Genetic testing in children described

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

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

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

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

Many symptoms are cardiomyopathy related

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

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

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

32 key messages derived from guidelines

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

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

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

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

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

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

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

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

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

Guidelines organize cardiomyopathy phenotypes

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

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

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

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

Genetic testing in children described

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

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

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

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

Many symptoms are cardiomyopathy related

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

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

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

32 key messages derived from guidelines

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

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

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

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

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

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

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

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

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

Guidelines organize cardiomyopathy phenotypes

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

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

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

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

Genetic testing in children described

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

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

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

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

Many symptoms are cardiomyopathy related

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

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

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

32 key messages derived from guidelines

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

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

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

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

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

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

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

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

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

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

No difference seen in primary outcome

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

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

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

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

Crossovers more common on minimal pacing

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

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

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

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

Results appear definitive

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

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

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

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

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

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

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

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

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

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

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

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

No difference seen in primary outcome

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

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

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

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

Crossovers more common on minimal pacing

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

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

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

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

Results appear definitive

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

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

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

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

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

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

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

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

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

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

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

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

No difference seen in primary outcome

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

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

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

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

Crossovers more common on minimal pacing

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

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

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

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

Results appear definitive

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

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

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

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

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

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

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

AURORA, COLO. – Several drugs for multiple sclerosis (MS) that are contraindicated during pregnancy nevertheless have not shown concerning safety signals in a series of small studies presented as posters at the annual meeting of the Consortium of Multiple Sclerosis Centers. The industry-sponsored research included an assessment of pregnancy and infant outcomes for cladribine, ocrelizumab, ofatumumab, and ozanimod, all of which are not recommended during pregnancy based primarily on minimal data that suggests, but does not confirm, possible teratogenicity.

“When these new medications hit the market, maternal-fetal medicine physicians and obstetricians are left with very scant data on how to counsel patients, and it’s often based on theory, case reports, or animal studies,” said Teodora Kolarova, MD, a maternal-fetal medicine physician at the University of Washington, Seattle, who was not involved in any of the research. “Although these sample sizes seem small, the population they are sampling from – patients with MS who take immunomodulators who then experience a pregnancy – is much smaller than all pregnant patients.”

Taken together, the findings suggest no increased risk of miscarriage or congenital malformation, compared with baseline risk, Dr. Kolarova said.

“As a whole, these studies are overall reassuring with, of course, some caveats, including timing of medication exposure, limited sample size, and limited outcome data,” Dr. Kolarova said. She noted that embryonic organ formation is complete by 10 weeks gestation, by which time an unplanned pregnancy may not have been recognized yet. “In the subset of patients in the studies that were exposed during the first trimester, there was no increase in congenital malformations from a baseline risk of about 2%-3% in the general population, which is helpful for patient counseling.”
 

Counseling during the childbearing years

That kind of counseling is important yet absent for many people capable of pregnancy, suggests separate research also presented at the conference by Suma Shah, MD, an associate professor of neurology at Duke University, Durham, N.C. Dr. Shah gave 13-question surveys to female MS patients of all ages at her institution and presented an analysis of data from 38 completed surveys. Among those taking disease-modifying therapies, their medications included ocrelizumab, rituximab, teriflunomide, fingolimod, fumarates, interferons, natalizumab, and cladribine.

“MS disproportionately impacts women among 20 to 40 years, and that’s a really big part of their childbearing years when there are big decisions being made about whether they’re going to choose to grow family or not,” said Dr. Shah. The average age of those who completed the survey was 44. Dr. Shah noted that a lot of research has looked at the safety of older disease-modifying agents in pregnancy, but that information doesn’t appear to be filtering down to patients. “What I really wanted to look at is what do our parent patients understand about whether or not they can even think about pregnancy – and there’s a lot of work to be done.”

Just under a third of survey respondents said they did not have as many children as they would like, and a quarter said they were told they couldn’t have children if they had a diagnosis of MS.

“That was a little heartbreaking to hear because that’s not the truth,” Dr. Shah said. She said it’s necessary to have a more detailed conversation looking at tailored decisions for patients. “Both of those things – patients not being able to grow their family to the number that they desire, and not feeling like they can grow a family – I would think in 2023 we would have come farther than that, and there’s still a lot of room there to improve.”

She advised clinicians not to assume that MS patients know what their options are regarding family planning. “There’s still a lot of room for conversations,” she said. She also explicitly recommends discussing family planning and pregnancy planning with every patient, no matter their gender, early and often.
 

Cladribine shows no miscarriage, malformations

Dr. Kolarova noted that one of the studies, on cladribine, had a fairly robust sample size with its 180 pregnancy exposures. In that study, led by Kerstin Hellwig, MD, of Ruhr University in Bochum, Germany, data came from the global surveillance program MAPLE-MS, established to assess cladribine effects on pregnancy and infant outcomes. The researchers analyzed data from 76 mothers and 9 fathers who, at any time from 2017 to 2022, were taking cladribine during pregnancy or up to 6 months before pregnancy. Outcomes included live birth, miscarriage, stillbirth, elective abortion, ectopic pregnancy, and major congenital anomalies.

Just over half the mothers (53.9%) were exposed before pregnancy, and about a quarter (26.3%) were exposed during the first trimester. The timing was unknown for most of the other mothers (18.4%). Among the fathers, two-thirds (66.7%) were exposed before pregnancy, and one-third had unknown timing.

Among the 180 pregnancies in the maternal cohort, 42.2% had known outcomes. Nearly half the women (48.7%) taking cladribine had live births, 28.9% had elective abortions, and 21.1% had miscarriages. Only 9 of the 22 pregnancies in the paternal cohort had known outcomes, which included 88.9% live births and 11.1% miscarriages. None of the pregnancies resulted in stillbirth or in a live birth with major congenital anomalies.

”Robust conclusions cannot be made about the risks of adverse pregnancy outcomes with cladribine tablets, but no increase has been signaled thus far,” the researchers reported. ”It is necessary to counsel patients to prevent pregnancy and to use effective contraception during cladribine tablets intake and for at least 6 months after the last cladribine tablet intake in each treatment year.”

Emily Evans, MD, MBE, medical director at U.S. Neurology and Immunology in Rockland, Mass., speaking on behalf of the findings, said they were fairly encouraging.

“Of course, we don’t encourage patients to get pregnant within 6 months of their last dose of cladribine tablets,” Dr. Evans said, but “within those individuals who have gotten pregnant within 6 months of their last dose of cladribine, or who have fathered a child within 6 months of their last dose of cladribine tablets, we’re seeing overall encouraging outcomes. We’re specifically not seeing any differences in the rates of spontaneous abortions, and we’re not seeing any differences in the rates of congenital malformations.”
 

Ocrelizumab and ofatumumab: No infections so far

Current recommendations for ocrelizumab are to avoid pregnancy for 6 months after the last infusion and stop any breastfeeding during therapy. Yet these recommendations are only because of insufficient data rather than evidence of risk, according to Lana Zhovtis Ryerson, MD, of the NYU Multiple Sclerosis Comprehensive Care Center in New York. She and her colleagues identified all women of childbearing age who had received ocrelizumab within 1 year of pregnancy at their NYU institution. A retrospective chart review found 18 women, with an average age of 35, an average 11 years of an MS diagnosis, and an average 11 months taking ocrelizumab.

Among the 18 pregnancies, four women had a first trimester miscarriage, one had a second trimester miscarriage, and one had an abortion. The miscarriage rate could have been partly influenced by the older maternal population, the authors noted. Of the remaining 12 live births, one infant was premature at 34 weeks, and three infants stayed in NICU but were discharged within 2 weeks.

One patient experienced an MS relapse postpartum, despite receiving ocrelizumab within 45 days of delivery. Of the 16 women who agreed to participate in a Pregnancy Assessment Monitoring System (PRAMS) developed by the CDC, two women chose to breastfeed, and seven said their neurologist recommended against breastfeeding. None of the children’s pediatricians advised delaying vaccinations.

“This small sample observational study has not identified a potential additional risk with ocrelizumab for an adverse pregnancy outcome,” the authors concluded, but they added that ongoing studies, MINORE and SOPRANINO, can help guide future recommendations.

Though still limited, slightly more data exists on ofatumumab during pregnancy, including transient B-cell depletion and lymphopenia in infants whose mothers received anti-CD20 antibodies during pregnancy. However, research has found minimal IgG transfer in the first trimester, though it begins rising in the second trimester, and in utero ofatumumab exposure did not lead to any maternal toxicity or adverse prenatal or postnatal developmental effects in cynomolgus monkeys.

Riley Love, MD, of the University of California, San Francisco, Weill Institute for Neuroscience, and her colleagues both prospectively and retrospectively examined pregnancy and infant outcomes for up to 1 year post partum in women with MS who took ofatumumab during pregnancy or in the 6 months leading up to pregnancy. Their population included 104 prospective cases, most of which (84%) included first trimester exposure, and 14 retrospective cases. One in five of the prospective cases occurred during a clinical trial, while the remaining 80% occurred in postmarketing surveillance.

The prospectively followed women were an average 32 years old and were an average 7 weeks pregnant at the time of reporting. Among the 106 fetuses (including two twin pregnancies), only 30 outcomes had data at the cutoff time, including 16 live births, 9 abortions, and 5 miscarriages. None of the live births had congenital anomalies or serious infections. Another 30 pregnancies were lost to follow-up, and 46 were ongoing.

In the 14 retrospective cases, 57% of women were exposed in the first trimester, and 43% were exposed leading up to pregnancy. Half the cases occurred during clinical trials, and half in postmarketing surveillance. The women were an average 32 years old and were an average 10 weeks pregnant at reporting. Among the 14 pregnancies, nine were miscarriages, one was aborted, and four were born live with no congenital anomalies.

The authors did not draw any conclusions from the findings; they cited too little data and an ongoing study by Novartis to investigate ofatumumab in pregnancy.

“Therapies such as ofatumumab and ocrelizumab can lead to increased risk of infection due to transient B-cell depletion in neonates, but the two studies looking at this did not demonstrate increased infectious morbidity for these infants,” Dr. Kolarova said. “As with all poster presentations, I look forward to reading the full papers once they are published as they will often include a lot more detail about when during pregnancy medication exposure occurred and more detailed outcome data that was assessed.”
 

Ozanimod outcomes within general population’s ‘expected ranges’

The final study looked at outcomes of pregnancies in people taking ozanimod and in the partners of people taking ozanimod in a clinical trial setting. The findings show low rates of miscarriage, preterm birth, and congenital anomalies that the authors concluded were within the typical range expected for the general population.

“While pregnancy should be avoided when taking and for 3 months after stopping ozanimod to allow for drug elimination, there is no evidence to date of increased occurrence of adverse pregnancy outcomes with ozanimod exposure during early pregnancy,” wrote Anthony Krakovich, of Bristol Myers Squibb in Princeton, N.J., and his associates.

Ozanimod is an oral sphingosine 1-phosphate (S1P) receptor 1 and 5 modulator whose therapeutic mechanism is not fully understood “but may involve the reduction of lymphocyte migration into the central nervous system and intestine,” the authors wrote. S1P receptors are involved in vascular formation during embryogenesis, and animal studies in rats and rabbits have shown toxicity to the embryo and fetus from S1P receptor modulators, including death and malformations. S1P receptor modulator labels therefore note potential fetal risk and the need for effective contraception while taking the drug.

The study prospectively tracked clinical trial participants taking ozanimod as healthy volunteers or for relapsing MS, ulcerative colitis, or Crohn’s disease. Most of the participants who became pregnant (73%) had relapsing MS, while 18% had ulcerative colitis and 8% had Crohn’s disease.

In female patients receiving ozanimod, 78 pregnancies resulted in 12 miscarriages (including one twin), 15 abortions, and 42 live births, with 6 pregnancies ongoing at the time of reporting and no data available for the remaining 4 pregnancies. Among the 42 live births, 4 were premature but otherwise healthy, 1 had a duplex kidney, and the other 37 infants were typical with no apparent health concerns. These rates of miscarriage, preterm birth, and congenital anomalies were within the expected ranges for the general population, the researchers wrote.

The researchers also assessed pregnancy outcomes for partners of male participants taking ozanimod. The 29 partner pregnancies resulted in 21 live births and one miscarriage, with one pregnancy ongoing and no information available for the other seven. The live births included 5 premature infants (including twins), 13 typical and healthy infants, 1 with Hirschsprung’s disease, 1 with a congenital hydrocele, and 1 with a partial atrioventricular septal defect. Again, the researchers concluded that these rates were within the typical range for the general population and that “no teratogenicity was observed.”

“We often encourage patients with MS, regardless of disease activity and therapies, to seek preconception evaluations with Maternal-Fetal Medicine and their neurologists in order to make plans for pregnancy and postpartum care,” Dr. Kolarova said. “That being said, access to subspecialized health care is not available to all, and pregnancy prior to such consultation does occur. These studies provide novel information that we have not had access to in the past and can improve patient counseling regarding their risks and options.”

The study on cladribine was funded by Merck KGaA, at which two authors are employed. Dr. Hellwig reported consulting, speaker, and/or research support from Bayer, Biogen, Teva, Novartis, Roche, Sanofi, Schering Healthcare, Serono, and Merck, and one author is a former employee of EMD Serono. The study on ocrelizumab was funded by Genentech. Dr. Zhovtis Ryerson reported personal fees from Biogen, Genentech, and Novartis, and research grants from Biogen, Genentech, and CMSC. The other authors had no disclosures. The study on ofatumumab was funded by Novartis. Dr. Bove has received research funds from Biogen, Novartis, and Roche Genentech, and consulting fees from EMD Serono, Horizon, Janssen, and TG Therapeutics; she has an ownership interest in Global Consult MD. Five authors are Novartis employees. Her coauthors, including Dr. Hellwig, reported advisory, consulting, research, speaking, or traveling fees from Alexion, Bayer, Biogen, Celgene BMS, EMD Serono, Horizon, Janssen, Lundbeck, Merck, Pfizer, Roche Genentech, Sanofi Genzyme, Schering Healthcare, Teva, TG Therapeutics, and Novartis. The study on ozanimod was funded by Bristol Myers Squibb. Dr. Krakovich and another author are employees and/or shareholders of Bristol Myers Squibb. The other authors reported consulting, speaking, advisory board, and/or research fees from AbbVie, Almirall, Arena, Biogen, Boehringer Ingelhei, Celgene, Celltrion, EXCEMED, Falk Benelux, Ferring, Forward Pharma, Genentech, Genzyme, Gilead, Janssen, Lilly, Merck, Novartis, Ono Pharma, Pfizer, Prometheus Labs, Protagonist, Roche, Sanofi, Synthon, Takeda, and Teva. Dr. Kolarova had no disclosures. Dr. Shah has received research support from Biogen and VeraSci.
 

AURORA, COLO. – Several drugs for multiple sclerosis (MS) that are contraindicated during pregnancy nevertheless have not shown concerning safety signals in a series of small studies presented as posters at the annual meeting of the Consortium of Multiple Sclerosis Centers. The industry-sponsored research included an assessment of pregnancy and infant outcomes for cladribine, ocrelizumab, ofatumumab, and ozanimod, all of which are not recommended during pregnancy based primarily on minimal data that suggests, but does not confirm, possible teratogenicity.

“When these new medications hit the market, maternal-fetal medicine physicians and obstetricians are left with very scant data on how to counsel patients, and it’s often based on theory, case reports, or animal studies,” said Teodora Kolarova, MD, a maternal-fetal medicine physician at the University of Washington, Seattle, who was not involved in any of the research. “Although these sample sizes seem small, the population they are sampling from – patients with MS who take immunomodulators who then experience a pregnancy – is much smaller than all pregnant patients.”

Taken together, the findings suggest no increased risk of miscarriage or congenital malformation, compared with baseline risk, Dr. Kolarova said.

“As a whole, these studies are overall reassuring with, of course, some caveats, including timing of medication exposure, limited sample size, and limited outcome data,” Dr. Kolarova said. She noted that embryonic organ formation is complete by 10 weeks gestation, by which time an unplanned pregnancy may not have been recognized yet. “In the subset of patients in the studies that were exposed during the first trimester, there was no increase in congenital malformations from a baseline risk of about 2%-3% in the general population, which is helpful for patient counseling.”
 

Counseling during the childbearing years

That kind of counseling is important yet absent for many people capable of pregnancy, suggests separate research also presented at the conference by Suma Shah, MD, an associate professor of neurology at Duke University, Durham, N.C. Dr. Shah gave 13-question surveys to female MS patients of all ages at her institution and presented an analysis of data from 38 completed surveys. Among those taking disease-modifying therapies, their medications included ocrelizumab, rituximab, teriflunomide, fingolimod, fumarates, interferons, natalizumab, and cladribine.

“MS disproportionately impacts women among 20 to 40 years, and that’s a really big part of their childbearing years when there are big decisions being made about whether they’re going to choose to grow family or not,” said Dr. Shah. The average age of those who completed the survey was 44. Dr. Shah noted that a lot of research has looked at the safety of older disease-modifying agents in pregnancy, but that information doesn’t appear to be filtering down to patients. “What I really wanted to look at is what do our parent patients understand about whether or not they can even think about pregnancy – and there’s a lot of work to be done.”

Just under a third of survey respondents said they did not have as many children as they would like, and a quarter said they were told they couldn’t have children if they had a diagnosis of MS.

“That was a little heartbreaking to hear because that’s not the truth,” Dr. Shah said. She said it’s necessary to have a more detailed conversation looking at tailored decisions for patients. “Both of those things – patients not being able to grow their family to the number that they desire, and not feeling like they can grow a family – I would think in 2023 we would have come farther than that, and there’s still a lot of room there to improve.”

She advised clinicians not to assume that MS patients know what their options are regarding family planning. “There’s still a lot of room for conversations,” she said. She also explicitly recommends discussing family planning and pregnancy planning with every patient, no matter their gender, early and often.
 

Cladribine shows no miscarriage, malformations

Dr. Kolarova noted that one of the studies, on cladribine, had a fairly robust sample size with its 180 pregnancy exposures. In that study, led by Kerstin Hellwig, MD, of Ruhr University in Bochum, Germany, data came from the global surveillance program MAPLE-MS, established to assess cladribine effects on pregnancy and infant outcomes. The researchers analyzed data from 76 mothers and 9 fathers who, at any time from 2017 to 2022, were taking cladribine during pregnancy or up to 6 months before pregnancy. Outcomes included live birth, miscarriage, stillbirth, elective abortion, ectopic pregnancy, and major congenital anomalies.

Just over half the mothers (53.9%) were exposed before pregnancy, and about a quarter (26.3%) were exposed during the first trimester. The timing was unknown for most of the other mothers (18.4%). Among the fathers, two-thirds (66.7%) were exposed before pregnancy, and one-third had unknown timing.

Among the 180 pregnancies in the maternal cohort, 42.2% had known outcomes. Nearly half the women (48.7%) taking cladribine had live births, 28.9% had elective abortions, and 21.1% had miscarriages. Only 9 of the 22 pregnancies in the paternal cohort had known outcomes, which included 88.9% live births and 11.1% miscarriages. None of the pregnancies resulted in stillbirth or in a live birth with major congenital anomalies.

”Robust conclusions cannot be made about the risks of adverse pregnancy outcomes with cladribine tablets, but no increase has been signaled thus far,” the researchers reported. ”It is necessary to counsel patients to prevent pregnancy and to use effective contraception during cladribine tablets intake and for at least 6 months after the last cladribine tablet intake in each treatment year.”

Emily Evans, MD, MBE, medical director at U.S. Neurology and Immunology in Rockland, Mass., speaking on behalf of the findings, said they were fairly encouraging.

“Of course, we don’t encourage patients to get pregnant within 6 months of their last dose of cladribine tablets,” Dr. Evans said, but “within those individuals who have gotten pregnant within 6 months of their last dose of cladribine, or who have fathered a child within 6 months of their last dose of cladribine tablets, we’re seeing overall encouraging outcomes. We’re specifically not seeing any differences in the rates of spontaneous abortions, and we’re not seeing any differences in the rates of congenital malformations.”
 

Ocrelizumab and ofatumumab: No infections so far

Current recommendations for ocrelizumab are to avoid pregnancy for 6 months after the last infusion and stop any breastfeeding during therapy. Yet these recommendations are only because of insufficient data rather than evidence of risk, according to Lana Zhovtis Ryerson, MD, of the NYU Multiple Sclerosis Comprehensive Care Center in New York. She and her colleagues identified all women of childbearing age who had received ocrelizumab within 1 year of pregnancy at their NYU institution. A retrospective chart review found 18 women, with an average age of 35, an average 11 years of an MS diagnosis, and an average 11 months taking ocrelizumab.

Among the 18 pregnancies, four women had a first trimester miscarriage, one had a second trimester miscarriage, and one had an abortion. The miscarriage rate could have been partly influenced by the older maternal population, the authors noted. Of the remaining 12 live births, one infant was premature at 34 weeks, and three infants stayed in NICU but were discharged within 2 weeks.

One patient experienced an MS relapse postpartum, despite receiving ocrelizumab within 45 days of delivery. Of the 16 women who agreed to participate in a Pregnancy Assessment Monitoring System (PRAMS) developed by the CDC, two women chose to breastfeed, and seven said their neurologist recommended against breastfeeding. None of the children’s pediatricians advised delaying vaccinations.

“This small sample observational study has not identified a potential additional risk with ocrelizumab for an adverse pregnancy outcome,” the authors concluded, but they added that ongoing studies, MINORE and SOPRANINO, can help guide future recommendations.

Though still limited, slightly more data exists on ofatumumab during pregnancy, including transient B-cell depletion and lymphopenia in infants whose mothers received anti-CD20 antibodies during pregnancy. However, research has found minimal IgG transfer in the first trimester, though it begins rising in the second trimester, and in utero ofatumumab exposure did not lead to any maternal toxicity or adverse prenatal or postnatal developmental effects in cynomolgus monkeys.

Riley Love, MD, of the University of California, San Francisco, Weill Institute for Neuroscience, and her colleagues both prospectively and retrospectively examined pregnancy and infant outcomes for up to 1 year post partum in women with MS who took ofatumumab during pregnancy or in the 6 months leading up to pregnancy. Their population included 104 prospective cases, most of which (84%) included first trimester exposure, and 14 retrospective cases. One in five of the prospective cases occurred during a clinical trial, while the remaining 80% occurred in postmarketing surveillance.

The prospectively followed women were an average 32 years old and were an average 7 weeks pregnant at the time of reporting. Among the 106 fetuses (including two twin pregnancies), only 30 outcomes had data at the cutoff time, including 16 live births, 9 abortions, and 5 miscarriages. None of the live births had congenital anomalies or serious infections. Another 30 pregnancies were lost to follow-up, and 46 were ongoing.

In the 14 retrospective cases, 57% of women were exposed in the first trimester, and 43% were exposed leading up to pregnancy. Half the cases occurred during clinical trials, and half in postmarketing surveillance. The women were an average 32 years old and were an average 10 weeks pregnant at reporting. Among the 14 pregnancies, nine were miscarriages, one was aborted, and four were born live with no congenital anomalies.

The authors did not draw any conclusions from the findings; they cited too little data and an ongoing study by Novartis to investigate ofatumumab in pregnancy.

“Therapies such as ofatumumab and ocrelizumab can lead to increased risk of infection due to transient B-cell depletion in neonates, but the two studies looking at this did not demonstrate increased infectious morbidity for these infants,” Dr. Kolarova said. “As with all poster presentations, I look forward to reading the full papers once they are published as they will often include a lot more detail about when during pregnancy medication exposure occurred and more detailed outcome data that was assessed.”
 

Ozanimod outcomes within general population’s ‘expected ranges’

The final study looked at outcomes of pregnancies in people taking ozanimod and in the partners of people taking ozanimod in a clinical trial setting. The findings show low rates of miscarriage, preterm birth, and congenital anomalies that the authors concluded were within the typical range expected for the general population.

“While pregnancy should be avoided when taking and for 3 months after stopping ozanimod to allow for drug elimination, there is no evidence to date of increased occurrence of adverse pregnancy outcomes with ozanimod exposure during early pregnancy,” wrote Anthony Krakovich, of Bristol Myers Squibb in Princeton, N.J., and his associates.

Ozanimod is an oral sphingosine 1-phosphate (S1P) receptor 1 and 5 modulator whose therapeutic mechanism is not fully understood “but may involve the reduction of lymphocyte migration into the central nervous system and intestine,” the authors wrote. S1P receptors are involved in vascular formation during embryogenesis, and animal studies in rats and rabbits have shown toxicity to the embryo and fetus from S1P receptor modulators, including death and malformations. S1P receptor modulator labels therefore note potential fetal risk and the need for effective contraception while taking the drug.

The study prospectively tracked clinical trial participants taking ozanimod as healthy volunteers or for relapsing MS, ulcerative colitis, or Crohn’s disease. Most of the participants who became pregnant (73%) had relapsing MS, while 18% had ulcerative colitis and 8% had Crohn’s disease.

In female patients receiving ozanimod, 78 pregnancies resulted in 12 miscarriages (including one twin), 15 abortions, and 42 live births, with 6 pregnancies ongoing at the time of reporting and no data available for the remaining 4 pregnancies. Among the 42 live births, 4 were premature but otherwise healthy, 1 had a duplex kidney, and the other 37 infants were typical with no apparent health concerns. These rates of miscarriage, preterm birth, and congenital anomalies were within the expected ranges for the general population, the researchers wrote.

The researchers also assessed pregnancy outcomes for partners of male participants taking ozanimod. The 29 partner pregnancies resulted in 21 live births and one miscarriage, with one pregnancy ongoing and no information available for the other seven. The live births included 5 premature infants (including twins), 13 typical and healthy infants, 1 with Hirschsprung’s disease, 1 with a congenital hydrocele, and 1 with a partial atrioventricular septal defect. Again, the researchers concluded that these rates were within the typical range for the general population and that “no teratogenicity was observed.”

“We often encourage patients with MS, regardless of disease activity and therapies, to seek preconception evaluations with Maternal-Fetal Medicine and their neurologists in order to make plans for pregnancy and postpartum care,” Dr. Kolarova said. “That being said, access to subspecialized health care is not available to all, and pregnancy prior to such consultation does occur. These studies provide novel information that we have not had access to in the past and can improve patient counseling regarding their risks and options.”

The study on cladribine was funded by Merck KGaA, at which two authors are employed. Dr. Hellwig reported consulting, speaker, and/or research support from Bayer, Biogen, Teva, Novartis, Roche, Sanofi, Schering Healthcare, Serono, and Merck, and one author is a former employee of EMD Serono. The study on ocrelizumab was funded by Genentech. Dr. Zhovtis Ryerson reported personal fees from Biogen, Genentech, and Novartis, and research grants from Biogen, Genentech, and CMSC. The other authors had no disclosures. The study on ofatumumab was funded by Novartis. Dr. Bove has received research funds from Biogen, Novartis, and Roche Genentech, and consulting fees from EMD Serono, Horizon, Janssen, and TG Therapeutics; she has an ownership interest in Global Consult MD. Five authors are Novartis employees. Her coauthors, including Dr. Hellwig, reported advisory, consulting, research, speaking, or traveling fees from Alexion, Bayer, Biogen, Celgene BMS, EMD Serono, Horizon, Janssen, Lundbeck, Merck, Pfizer, Roche Genentech, Sanofi Genzyme, Schering Healthcare, Teva, TG Therapeutics, and Novartis. The study on ozanimod was funded by Bristol Myers Squibb. Dr. Krakovich and another author are employees and/or shareholders of Bristol Myers Squibb. The other authors reported consulting, speaking, advisory board, and/or research fees from AbbVie, Almirall, Arena, Biogen, Boehringer Ingelhei, Celgene, Celltrion, EXCEMED, Falk Benelux, Ferring, Forward Pharma, Genentech, Genzyme, Gilead, Janssen, Lilly, Merck, Novartis, Ono Pharma, Pfizer, Prometheus Labs, Protagonist, Roche, Sanofi, Synthon, Takeda, and Teva. Dr. Kolarova had no disclosures. Dr. Shah has received research support from Biogen and VeraSci.
 

AURORA, COLO. – Several drugs for multiple sclerosis (MS) that are contraindicated during pregnancy nevertheless have not shown concerning safety signals in a series of small studies presented as posters at the annual meeting of the Consortium of Multiple Sclerosis Centers. The industry-sponsored research included an assessment of pregnancy and infant outcomes for cladribine, ocrelizumab, ofatumumab, and ozanimod, all of which are not recommended during pregnancy based primarily on minimal data that suggests, but does not confirm, possible teratogenicity.

“When these new medications hit the market, maternal-fetal medicine physicians and obstetricians are left with very scant data on how to counsel patients, and it’s often based on theory, case reports, or animal studies,” said Teodora Kolarova, MD, a maternal-fetal medicine physician at the University of Washington, Seattle, who was not involved in any of the research. “Although these sample sizes seem small, the population they are sampling from – patients with MS who take immunomodulators who then experience a pregnancy – is much smaller than all pregnant patients.”

Taken together, the findings suggest no increased risk of miscarriage or congenital malformation, compared with baseline risk, Dr. Kolarova said.

“As a whole, these studies are overall reassuring with, of course, some caveats, including timing of medication exposure, limited sample size, and limited outcome data,” Dr. Kolarova said. She noted that embryonic organ formation is complete by 10 weeks gestation, by which time an unplanned pregnancy may not have been recognized yet. “In the subset of patients in the studies that were exposed during the first trimester, there was no increase in congenital malformations from a baseline risk of about 2%-3% in the general population, which is helpful for patient counseling.”
 

Counseling during the childbearing years

That kind of counseling is important yet absent for many people capable of pregnancy, suggests separate research also presented at the conference by Suma Shah, MD, an associate professor of neurology at Duke University, Durham, N.C. Dr. Shah gave 13-question surveys to female MS patients of all ages at her institution and presented an analysis of data from 38 completed surveys. Among those taking disease-modifying therapies, their medications included ocrelizumab, rituximab, teriflunomide, fingolimod, fumarates, interferons, natalizumab, and cladribine.

“MS disproportionately impacts women among 20 to 40 years, and that’s a really big part of their childbearing years when there are big decisions being made about whether they’re going to choose to grow family or not,” said Dr. Shah. The average age of those who completed the survey was 44. Dr. Shah noted that a lot of research has looked at the safety of older disease-modifying agents in pregnancy, but that information doesn’t appear to be filtering down to patients. “What I really wanted to look at is what do our parent patients understand about whether or not they can even think about pregnancy – and there’s a lot of work to be done.”

Just under a third of survey respondents said they did not have as many children as they would like, and a quarter said they were told they couldn’t have children if they had a diagnosis of MS.

“That was a little heartbreaking to hear because that’s not the truth,” Dr. Shah said. She said it’s necessary to have a more detailed conversation looking at tailored decisions for patients. “Both of those things – patients not being able to grow their family to the number that they desire, and not feeling like they can grow a family – I would think in 2023 we would have come farther than that, and there’s still a lot of room there to improve.”

She advised clinicians not to assume that MS patients know what their options are regarding family planning. “There’s still a lot of room for conversations,” she said. She also explicitly recommends discussing family planning and pregnancy planning with every patient, no matter their gender, early and often.
 

Cladribine shows no miscarriage, malformations

Dr. Kolarova noted that one of the studies, on cladribine, had a fairly robust sample size with its 180 pregnancy exposures. In that study, led by Kerstin Hellwig, MD, of Ruhr University in Bochum, Germany, data came from the global surveillance program MAPLE-MS, established to assess cladribine effects on pregnancy and infant outcomes. The researchers analyzed data from 76 mothers and 9 fathers who, at any time from 2017 to 2022, were taking cladribine during pregnancy or up to 6 months before pregnancy. Outcomes included live birth, miscarriage, stillbirth, elective abortion, ectopic pregnancy, and major congenital anomalies.

Just over half the mothers (53.9%) were exposed before pregnancy, and about a quarter (26.3%) were exposed during the first trimester. The timing was unknown for most of the other mothers (18.4%). Among the fathers, two-thirds (66.7%) were exposed before pregnancy, and one-third had unknown timing.

Among the 180 pregnancies in the maternal cohort, 42.2% had known outcomes. Nearly half the women (48.7%) taking cladribine had live births, 28.9% had elective abortions, and 21.1% had miscarriages. Only 9 of the 22 pregnancies in the paternal cohort had known outcomes, which included 88.9% live births and 11.1% miscarriages. None of the pregnancies resulted in stillbirth or in a live birth with major congenital anomalies.

”Robust conclusions cannot be made about the risks of adverse pregnancy outcomes with cladribine tablets, but no increase has been signaled thus far,” the researchers reported. ”It is necessary to counsel patients to prevent pregnancy and to use effective contraception during cladribine tablets intake and for at least 6 months after the last cladribine tablet intake in each treatment year.”

Emily Evans, MD, MBE, medical director at U.S. Neurology and Immunology in Rockland, Mass., speaking on behalf of the findings, said they were fairly encouraging.

“Of course, we don’t encourage patients to get pregnant within 6 months of their last dose of cladribine tablets,” Dr. Evans said, but “within those individuals who have gotten pregnant within 6 months of their last dose of cladribine, or who have fathered a child within 6 months of their last dose of cladribine tablets, we’re seeing overall encouraging outcomes. We’re specifically not seeing any differences in the rates of spontaneous abortions, and we’re not seeing any differences in the rates of congenital malformations.”
 

Ocrelizumab and ofatumumab: No infections so far

Current recommendations for ocrelizumab are to avoid pregnancy for 6 months after the last infusion and stop any breastfeeding during therapy. Yet these recommendations are only because of insufficient data rather than evidence of risk, according to Lana Zhovtis Ryerson, MD, of the NYU Multiple Sclerosis Comprehensive Care Center in New York. She and her colleagues identified all women of childbearing age who had received ocrelizumab within 1 year of pregnancy at their NYU institution. A retrospective chart review found 18 women, with an average age of 35, an average 11 years of an MS diagnosis, and an average 11 months taking ocrelizumab.

Among the 18 pregnancies, four women had a first trimester miscarriage, one had a second trimester miscarriage, and one had an abortion. The miscarriage rate could have been partly influenced by the older maternal population, the authors noted. Of the remaining 12 live births, one infant was premature at 34 weeks, and three infants stayed in NICU but were discharged within 2 weeks.

One patient experienced an MS relapse postpartum, despite receiving ocrelizumab within 45 days of delivery. Of the 16 women who agreed to participate in a Pregnancy Assessment Monitoring System (PRAMS) developed by the CDC, two women chose to breastfeed, and seven said their neurologist recommended against breastfeeding. None of the children’s pediatricians advised delaying vaccinations.

“This small sample observational study has not identified a potential additional risk with ocrelizumab for an adverse pregnancy outcome,” the authors concluded, but they added that ongoing studies, MINORE and SOPRANINO, can help guide future recommendations.

Though still limited, slightly more data exists on ofatumumab during pregnancy, including transient B-cell depletion and lymphopenia in infants whose mothers received anti-CD20 antibodies during pregnancy. However, research has found minimal IgG transfer in the first trimester, though it begins rising in the second trimester, and in utero ofatumumab exposure did not lead to any maternal toxicity or adverse prenatal or postnatal developmental effects in cynomolgus monkeys.

Riley Love, MD, of the University of California, San Francisco, Weill Institute for Neuroscience, and her colleagues both prospectively and retrospectively examined pregnancy and infant outcomes for up to 1 year post partum in women with MS who took ofatumumab during pregnancy or in the 6 months leading up to pregnancy. Their population included 104 prospective cases, most of which (84%) included first trimester exposure, and 14 retrospective cases. One in five of the prospective cases occurred during a clinical trial, while the remaining 80% occurred in postmarketing surveillance.

The prospectively followed women were an average 32 years old and were an average 7 weeks pregnant at the time of reporting. Among the 106 fetuses (including two twin pregnancies), only 30 outcomes had data at the cutoff time, including 16 live births, 9 abortions, and 5 miscarriages. None of the live births had congenital anomalies or serious infections. Another 30 pregnancies were lost to follow-up, and 46 were ongoing.

In the 14 retrospective cases, 57% of women were exposed in the first trimester, and 43% were exposed leading up to pregnancy. Half the cases occurred during clinical trials, and half in postmarketing surveillance. The women were an average 32 years old and were an average 10 weeks pregnant at reporting. Among the 14 pregnancies, nine were miscarriages, one was aborted, and four were born live with no congenital anomalies.

The authors did not draw any conclusions from the findings; they cited too little data and an ongoing study by Novartis to investigate ofatumumab in pregnancy.

“Therapies such as ofatumumab and ocrelizumab can lead to increased risk of infection due to transient B-cell depletion in neonates, but the two studies looking at this did not demonstrate increased infectious morbidity for these infants,” Dr. Kolarova said. “As with all poster presentations, I look forward to reading the full papers once they are published as they will often include a lot more detail about when during pregnancy medication exposure occurred and more detailed outcome data that was assessed.”
 

Ozanimod outcomes within general population’s ‘expected ranges’

The final study looked at outcomes of pregnancies in people taking ozanimod and in the partners of people taking ozanimod in a clinical trial setting. The findings show low rates of miscarriage, preterm birth, and congenital anomalies that the authors concluded were within the typical range expected for the general population.

“While pregnancy should be avoided when taking and for 3 months after stopping ozanimod to allow for drug elimination, there is no evidence to date of increased occurrence of adverse pregnancy outcomes with ozanimod exposure during early pregnancy,” wrote Anthony Krakovich, of Bristol Myers Squibb in Princeton, N.J., and his associates.

Ozanimod is an oral sphingosine 1-phosphate (S1P) receptor 1 and 5 modulator whose therapeutic mechanism is not fully understood “but may involve the reduction of lymphocyte migration into the central nervous system and intestine,” the authors wrote. S1P receptors are involved in vascular formation during embryogenesis, and animal studies in rats and rabbits have shown toxicity to the embryo and fetus from S1P receptor modulators, including death and malformations. S1P receptor modulator labels therefore note potential fetal risk and the need for effective contraception while taking the drug.

The study prospectively tracked clinical trial participants taking ozanimod as healthy volunteers or for relapsing MS, ulcerative colitis, or Crohn’s disease. Most of the participants who became pregnant (73%) had relapsing MS, while 18% had ulcerative colitis and 8% had Crohn’s disease.

In female patients receiving ozanimod, 78 pregnancies resulted in 12 miscarriages (including one twin), 15 abortions, and 42 live births, with 6 pregnancies ongoing at the time of reporting and no data available for the remaining 4 pregnancies. Among the 42 live births, 4 were premature but otherwise healthy, 1 had a duplex kidney, and the other 37 infants were typical with no apparent health concerns. These rates of miscarriage, preterm birth, and congenital anomalies were within the expected ranges for the general population, the researchers wrote.

The researchers also assessed pregnancy outcomes for partners of male participants taking ozanimod. The 29 partner pregnancies resulted in 21 live births and one miscarriage, with one pregnancy ongoing and no information available for the other seven. The live births included 5 premature infants (including twins), 13 typical and healthy infants, 1 with Hirschsprung’s disease, 1 with a congenital hydrocele, and 1 with a partial atrioventricular septal defect. Again, the researchers concluded that these rates were within the typical range for the general population and that “no teratogenicity was observed.”

“We often encourage patients with MS, regardless of disease activity and therapies, to seek preconception evaluations with Maternal-Fetal Medicine and their neurologists in order to make plans for pregnancy and postpartum care,” Dr. Kolarova said. “That being said, access to subspecialized health care is not available to all, and pregnancy prior to such consultation does occur. These studies provide novel information that we have not had access to in the past and can improve patient counseling regarding their risks and options.”

The study on cladribine was funded by Merck KGaA, at which two authors are employed. Dr. Hellwig reported consulting, speaker, and/or research support from Bayer, Biogen, Teva, Novartis, Roche, Sanofi, Schering Healthcare, Serono, and Merck, and one author is a former employee of EMD Serono. The study on ocrelizumab was funded by Genentech. Dr. Zhovtis Ryerson reported personal fees from Biogen, Genentech, and Novartis, and research grants from Biogen, Genentech, and CMSC. The other authors had no disclosures. The study on ofatumumab was funded by Novartis. Dr. Bove has received research funds from Biogen, Novartis, and Roche Genentech, and consulting fees from EMD Serono, Horizon, Janssen, and TG Therapeutics; she has an ownership interest in Global Consult MD. Five authors are Novartis employees. Her coauthors, including Dr. Hellwig, reported advisory, consulting, research, speaking, or traveling fees from Alexion, Bayer, Biogen, Celgene BMS, EMD Serono, Horizon, Janssen, Lundbeck, Merck, Pfizer, Roche Genentech, Sanofi Genzyme, Schering Healthcare, Teva, TG Therapeutics, and Novartis. The study on ozanimod was funded by Bristol Myers Squibb. Dr. Krakovich and another author are employees and/or shareholders of Bristol Myers Squibb. The other authors reported consulting, speaking, advisory board, and/or research fees from AbbVie, Almirall, Arena, Biogen, Boehringer Ingelhei, Celgene, Celltrion, EXCEMED, Falk Benelux, Ferring, Forward Pharma, Genentech, Genzyme, Gilead, Janssen, Lilly, Merck, Novartis, Ono Pharma, Pfizer, Prometheus Labs, Protagonist, Roche, Sanofi, Synthon, Takeda, and Teva. Dr. Kolarova had no disclosures. Dr. Shah has received research support from Biogen and VeraSci.
 

Low-dose aspirin reduces the risk for type 2 diabetes among older adults and slows the increase in fasting glucose levels over time, new research finds.

The data come from a secondary analysis of ASPREE, a double-blind, placebo-controlled trial of healthy adults aged 65 years or older, showing that 100 mg of aspirin taken daily for about 5 years did not provide a cardiovascular benefit but did significantly raise the risk for bleeding.

This new analysis shows that individuals taking aspirin had a 15% lower risk for developing type 2 diabetes and that the medication slowed the rate of increase in fasting plasma glucose, compared with placebo, during follow-up.

However, lead author Sophia Zoungas, MBBS, PhD, head of the School of Public Health and Preventive Medicine, Monash University, Melbourne, said: “Major prescribing guidelines now recommend older adults take daily aspirin only when there is a medical reason to do so, such as after a heart attack. ... Although these new findings are of interest, they do not change the clinical advice about aspirin use in older people at this time.”

Nonetheless, she said in an interview, “at this time, our findings are exploratory but ignite the debate of the important role that anti-inflammatory approaches may play in preventing diabetes. Further work is currently underway to understand which subpopulations may be better targeted and to understand the balance of risk versus benefit.”

The results are scheduled to be presented at the upcoming meeting of the European Association for the Study of Diabetes, taking place Oct. 2-6 in Hamburg, Germany.
 

New findings not robust enough to change current practice

Asked to comment, Debabrata Mukherjee, MD, said: “Given the post hoc secondary nature of the analysis, the findings should be considered hypothesis generating and not definitive… At this time, based on prospective randomized studies, the risks of aspirin outweigh the benefits for aspirin in older adults.”

Among those studies was an ASPREE substudy showing failure of low-dose aspirin to reduce fracture risk while increasing the risk for serious falls, and two other trials, ARRIVE and ASCEND, also showing that harms of aspirin outweigh the benefits in people with cardiovascular risk but not diabetes, and in those with diabetes, respectively, said Dr. Mukherjee, professor and chair of the department of internal medicine at Texas Tech University Health Sciences Center at El Paso.

And, Mukherjee noted, in 2019 the American College of Cardiology updated its practice guidelines to say that low-dose aspirin should not be administered on a routine basis for the primary prevention of atherosclerotic cardiovascular disease in adults over age 70. In 2021, the American Diabetes Association seconded that recommendation.

Asked whether these newest findings might change current practice for any higher-risk subgroup, such as people with prediabetes, Dr. Mukherjee replied: “Unless there is a prospective randomized trial that validates these findings in those with prediabetes, the findings should not change practice. There are also no data [showing] that another antiplatelet agent would be indicated or would be beneficial. Instead, I would recommend lifestyle changes including regular exercise and a healthy diet to minimize risk of diabetes.”

The 16,209 ASPREE participants were community dwelling and did not have diabetes, cardiovascular disease, or dementia at baseline. They were randomized in a 1:1 ratio to receive 100 mg/d of enteric-coated aspirin or placebo. Over a median follow-up of 4.7 years, the proportions developing type 2 diabetes were 5.7% with aspirin versus 6.6% with placebo (hazard ratio, 0.85; P = .01).

The annual rate of increase in fasting plasma glucose over the follow-up period was slowed by 0.006 mmol/L with aspirin, compared with placebo, also a significant difference (P = .004).

According to Dr. Zoungas, “the potential for anti-inflammatory agents like aspirin to prevent type 2 diabetes or improve glucose levels needs further study.”

The ASPREE trial was supported by the U.S. National Institutes of Health, the National Health and Medical Research Council of Australia, Monash University, and the Victorian Cancer Agency. Dr. Zoungas and Dr. Mukherjee have no disclosures.

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

Low-dose aspirin reduces the risk for type 2 diabetes among older adults and slows the increase in fasting glucose levels over time, new research finds.

The data come from a secondary analysis of ASPREE, a double-blind, placebo-controlled trial of healthy adults aged 65 years or older, showing that 100 mg of aspirin taken daily for about 5 years did not provide a cardiovascular benefit but did significantly raise the risk for bleeding.

This new analysis shows that individuals taking aspirin had a 15% lower risk for developing type 2 diabetes and that the medication slowed the rate of increase in fasting plasma glucose, compared with placebo, during follow-up.

However, lead author Sophia Zoungas, MBBS, PhD, head of the School of Public Health and Preventive Medicine, Monash University, Melbourne, said: “Major prescribing guidelines now recommend older adults take daily aspirin only when there is a medical reason to do so, such as after a heart attack. ... Although these new findings are of interest, they do not change the clinical advice about aspirin use in older people at this time.”

Nonetheless, she said in an interview, “at this time, our findings are exploratory but ignite the debate of the important role that anti-inflammatory approaches may play in preventing diabetes. Further work is currently underway to understand which subpopulations may be better targeted and to understand the balance of risk versus benefit.”

The results are scheduled to be presented at the upcoming meeting of the European Association for the Study of Diabetes, taking place Oct. 2-6 in Hamburg, Germany.
 

New findings not robust enough to change current practice

Asked to comment, Debabrata Mukherjee, MD, said: “Given the post hoc secondary nature of the analysis, the findings should be considered hypothesis generating and not definitive… At this time, based on prospective randomized studies, the risks of aspirin outweigh the benefits for aspirin in older adults.”

Among those studies was an ASPREE substudy showing failure of low-dose aspirin to reduce fracture risk while increasing the risk for serious falls, and two other trials, ARRIVE and ASCEND, also showing that harms of aspirin outweigh the benefits in people with cardiovascular risk but not diabetes, and in those with diabetes, respectively, said Dr. Mukherjee, professor and chair of the department of internal medicine at Texas Tech University Health Sciences Center at El Paso.

And, Mukherjee noted, in 2019 the American College of Cardiology updated its practice guidelines to say that low-dose aspirin should not be administered on a routine basis for the primary prevention of atherosclerotic cardiovascular disease in adults over age 70. In 2021, the American Diabetes Association seconded that recommendation.

Asked whether these newest findings might change current practice for any higher-risk subgroup, such as people with prediabetes, Dr. Mukherjee replied: “Unless there is a prospective randomized trial that validates these findings in those with prediabetes, the findings should not change practice. There are also no data [showing] that another antiplatelet agent would be indicated or would be beneficial. Instead, I would recommend lifestyle changes including regular exercise and a healthy diet to minimize risk of diabetes.”

The 16,209 ASPREE participants were community dwelling and did not have diabetes, cardiovascular disease, or dementia at baseline. They were randomized in a 1:1 ratio to receive 100 mg/d of enteric-coated aspirin or placebo. Over a median follow-up of 4.7 years, the proportions developing type 2 diabetes were 5.7% with aspirin versus 6.6% with placebo (hazard ratio, 0.85; P = .01).

The annual rate of increase in fasting plasma glucose over the follow-up period was slowed by 0.006 mmol/L with aspirin, compared with placebo, also a significant difference (P = .004).

According to Dr. Zoungas, “the potential for anti-inflammatory agents like aspirin to prevent type 2 diabetes or improve glucose levels needs further study.”

The ASPREE trial was supported by the U.S. National Institutes of Health, the National Health and Medical Research Council of Australia, Monash University, and the Victorian Cancer Agency. Dr. Zoungas and Dr. Mukherjee have no disclosures.

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

Low-dose aspirin reduces the risk for type 2 diabetes among older adults and slows the increase in fasting glucose levels over time, new research finds.

The data come from a secondary analysis of ASPREE, a double-blind, placebo-controlled trial of healthy adults aged 65 years or older, showing that 100 mg of aspirin taken daily for about 5 years did not provide a cardiovascular benefit but did significantly raise the risk for bleeding.

This new analysis shows that individuals taking aspirin had a 15% lower risk for developing type 2 diabetes and that the medication slowed the rate of increase in fasting plasma glucose, compared with placebo, during follow-up.

However, lead author Sophia Zoungas, MBBS, PhD, head of the School of Public Health and Preventive Medicine, Monash University, Melbourne, said: “Major prescribing guidelines now recommend older adults take daily aspirin only when there is a medical reason to do so, such as after a heart attack. ... Although these new findings are of interest, they do not change the clinical advice about aspirin use in older people at this time.”

Nonetheless, she said in an interview, “at this time, our findings are exploratory but ignite the debate of the important role that anti-inflammatory approaches may play in preventing diabetes. Further work is currently underway to understand which subpopulations may be better targeted and to understand the balance of risk versus benefit.”

The results are scheduled to be presented at the upcoming meeting of the European Association for the Study of Diabetes, taking place Oct. 2-6 in Hamburg, Germany.
 

New findings not robust enough to change current practice

Asked to comment, Debabrata Mukherjee, MD, said: “Given the post hoc secondary nature of the analysis, the findings should be considered hypothesis generating and not definitive… At this time, based on prospective randomized studies, the risks of aspirin outweigh the benefits for aspirin in older adults.”

Among those studies was an ASPREE substudy showing failure of low-dose aspirin to reduce fracture risk while increasing the risk for serious falls, and two other trials, ARRIVE and ASCEND, also showing that harms of aspirin outweigh the benefits in people with cardiovascular risk but not diabetes, and in those with diabetes, respectively, said Dr. Mukherjee, professor and chair of the department of internal medicine at Texas Tech University Health Sciences Center at El Paso.

And, Mukherjee noted, in 2019 the American College of Cardiology updated its practice guidelines to say that low-dose aspirin should not be administered on a routine basis for the primary prevention of atherosclerotic cardiovascular disease in adults over age 70. In 2021, the American Diabetes Association seconded that recommendation.

Asked whether these newest findings might change current practice for any higher-risk subgroup, such as people with prediabetes, Dr. Mukherjee replied: “Unless there is a prospective randomized trial that validates these findings in those with prediabetes, the findings should not change practice. There are also no data [showing] that another antiplatelet agent would be indicated or would be beneficial. Instead, I would recommend lifestyle changes including regular exercise and a healthy diet to minimize risk of diabetes.”

The 16,209 ASPREE participants were community dwelling and did not have diabetes, cardiovascular disease, or dementia at baseline. They were randomized in a 1:1 ratio to receive 100 mg/d of enteric-coated aspirin or placebo. Over a median follow-up of 4.7 years, the proportions developing type 2 diabetes were 5.7% with aspirin versus 6.6% with placebo (hazard ratio, 0.85; P = .01).

The annual rate of increase in fasting plasma glucose over the follow-up period was slowed by 0.006 mmol/L with aspirin, compared with placebo, also a significant difference (P = .004).

According to Dr. Zoungas, “the potential for anti-inflammatory agents like aspirin to prevent type 2 diabetes or improve glucose levels needs further study.”

The ASPREE trial was supported by the U.S. National Institutes of Health, the National Health and Medical Research Council of Australia, Monash University, and the Victorian Cancer Agency. Dr. Zoungas and Dr. Mukherjee have no disclosures.

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

SAN DIEGO – When the Boston-based cosmetic dermatology practice that employed Catherine M. DiGiorgio, MD, MS, was sold to a private equity firm a few years ago, she found herself at a crossroads: Stay and work for a large corporation, or open a solo practice?

She opted to start her own practice in Boston, “because I didn’t want to work for a large corporation, and I want to provide the best care for my patients in a more intimate manner,” Dr. DiGiorgio, a board-certified laser and cosmetic dermatologist, said at the annual Masters of Aesthetics Symposium.

Dr. DiGiorgio

The decision also tested her mettle. “I spoke to several colleagues and friends, and I was terrified,” she said. “I was like: ‘I don’t even know where to start.’ ”

On the heels of opening a new office in a matter of weeks, she offered the following tips and questions to consider when launching a solo dermatology practice:

Select a location. “That’s your first decision,” she said. “Where in the city are you going to open? Are you going to a new city, or are you moving back home? Don’t be afraid to start from scratch, and don’t be afraid to start a [solo] practice if you already have a patient base.”

Will you lease or purchase your space? After she secured a bank loan, Dr. DiGiorgio chose to lease the space for her new practice, “because you can kind of see where things go, get all the kinks out and figure out how to build things in a space that you don’t own. Then, when you’re ready and you have grown, you can invest more into your practice.”

Will you accept insurance? She built her practice around the direct specialty care model, which emphasizes the patient-physician relationship and removes third-party payors. “It’s not a concierge practice, but it’s a transparent, reasonable fee schedule for medical dermatology,” she explained. “I’ve done 100% cosmetics for about 5 years now, [but] I do medical dermatology for a fee. On my website I have a full price list on how much a full skin check is, [and] how much biopsies are. It’s completely transparent. Patients can submit to their insurance for reimbursement, but we don’t guarantee that they’re going to be reimbursed.”

Where will your patients come from? Will you advertise? Do you have physicians in the area who will refer to you if you’re a board-certified dermatologist? She emphasized the importance of “learning how to present yourself” on a website dedicated to your own practice. “Instagram, Facebook, and social media are great, but you don’t own those pages,” noted Dr. DiGiorgio, who served as the program cochair of the 2023 annual meeting of the American Society for Laser Medicine and Surgery and was recently elected to serve on the board of directors for the American Society for Dermatology Surgery. “You don’t own one of those pictures that are posted on your social media page. They can disappear in a second. If that happens, how are people going to find you?”

Are you going to hire more physicians in the future? That will influence the size of the new office and the floor plan.

Lawyer up. Hiring a health care attorney can “help you navigate transitioning from whatever position you’re in to opening up your own practice, as well as setting up the regulatory paperwork necessary for your new practice. You’ll also need a real estate attorney to help once you have selected a place, to help you navigate through that process,” she said, such as figuring out if the elevator in the building meets the Americans With Disabilities Act (ADA) requirements.

Create a mission statement. That way, “you know why you’re doing this, and it stays with you as you’re getting through the hard roadblocks.”

Find an architect, contractor, or designer. “If you’re building out a space from scratch, you’re going to need an architect,” she said. “Along with that architect will come a full-on contracting firm. I ended up hiring everyone individually, because I’m trying to spend as little money as possible.” She also hired a designer to help select furnishings and create the office atmosphere.

Secure a building permit ASAP. “It’s almost better to have the city permit before you sign the lease, because the permits can take a year, and you don’t want to pay rent on an empty space for a year if you don’t have a permit or if there are other hoops to go through,” Dr. DiGiorgio said.

Find an agent to help you set up medical malpractice insurance, liability insurance, and worker’s compensation insurance. “Make sure you read all the paperwork, because it can be very intricate,” she said.

Find an accountant. That person can help set up a bookkeeping process.

What equipment and devices will you need? That depends largely on the patient population a physician serves. Dr. DiGiorgio noted that eligible small businesses may take a tax credit of up to $5,000 per year for accommodations made to comply with the ADA. “That’s a nice feature, so that you can purchase ADA compliant items like a larger exam chair and custom reception areas.”

Dr. DiGiorgio reported having no relevant disclosures.

SAN DIEGO – When the Boston-based cosmetic dermatology practice that employed Catherine M. DiGiorgio, MD, MS, was sold to a private equity firm a few years ago, she found herself at a crossroads: Stay and work for a large corporation, or open a solo practice?

She opted to start her own practice in Boston, “because I didn’t want to work for a large corporation, and I want to provide the best care for my patients in a more intimate manner,” Dr. DiGiorgio, a board-certified laser and cosmetic dermatologist, said at the annual Masters of Aesthetics Symposium.

Dr. DiGiorgio

The decision also tested her mettle. “I spoke to several colleagues and friends, and I was terrified,” she said. “I was like: ‘I don’t even know where to start.’ ”

On the heels of opening a new office in a matter of weeks, she offered the following tips and questions to consider when launching a solo dermatology practice:

Select a location. “That’s your first decision,” she said. “Where in the city are you going to open? Are you going to a new city, or are you moving back home? Don’t be afraid to start from scratch, and don’t be afraid to start a [solo] practice if you already have a patient base.”

Will you lease or purchase your space? After she secured a bank loan, Dr. DiGiorgio chose to lease the space for her new practice, “because you can kind of see where things go, get all the kinks out and figure out how to build things in a space that you don’t own. Then, when you’re ready and you have grown, you can invest more into your practice.”

Will you accept insurance? She built her practice around the direct specialty care model, which emphasizes the patient-physician relationship and removes third-party payors. “It’s not a concierge practice, but it’s a transparent, reasonable fee schedule for medical dermatology,” she explained. “I’ve done 100% cosmetics for about 5 years now, [but] I do medical dermatology for a fee. On my website I have a full price list on how much a full skin check is, [and] how much biopsies are. It’s completely transparent. Patients can submit to their insurance for reimbursement, but we don’t guarantee that they’re going to be reimbursed.”

Where will your patients come from? Will you advertise? Do you have physicians in the area who will refer to you if you’re a board-certified dermatologist? She emphasized the importance of “learning how to present yourself” on a website dedicated to your own practice. “Instagram, Facebook, and social media are great, but you don’t own those pages,” noted Dr. DiGiorgio, who served as the program cochair of the 2023 annual meeting of the American Society for Laser Medicine and Surgery and was recently elected to serve on the board of directors for the American Society for Dermatology Surgery. “You don’t own one of those pictures that are posted on your social media page. They can disappear in a second. If that happens, how are people going to find you?”

Are you going to hire more physicians in the future? That will influence the size of the new office and the floor plan.

Lawyer up. Hiring a health care attorney can “help you navigate transitioning from whatever position you’re in to opening up your own practice, as well as setting up the regulatory paperwork necessary for your new practice. You’ll also need a real estate attorney to help once you have selected a place, to help you navigate through that process,” she said, such as figuring out if the elevator in the building meets the Americans With Disabilities Act (ADA) requirements.

Create a mission statement. That way, “you know why you’re doing this, and it stays with you as you’re getting through the hard roadblocks.”

Find an architect, contractor, or designer. “If you’re building out a space from scratch, you’re going to need an architect,” she said. “Along with that architect will come a full-on contracting firm. I ended up hiring everyone individually, because I’m trying to spend as little money as possible.” She also hired a designer to help select furnishings and create the office atmosphere.

Secure a building permit ASAP. “It’s almost better to have the city permit before you sign the lease, because the permits can take a year, and you don’t want to pay rent on an empty space for a year if you don’t have a permit or if there are other hoops to go through,” Dr. DiGiorgio said.

Find an agent to help you set up medical malpractice insurance, liability insurance, and worker’s compensation insurance. “Make sure you read all the paperwork, because it can be very intricate,” she said.

Find an accountant. That person can help set up a bookkeeping process.

What equipment and devices will you need? That depends largely on the patient population a physician serves. Dr. DiGiorgio noted that eligible small businesses may take a tax credit of up to $5,000 per year for accommodations made to comply with the ADA. “That’s a nice feature, so that you can purchase ADA compliant items like a larger exam chair and custom reception areas.”

Dr. DiGiorgio reported having no relevant disclosures.

SAN DIEGO – When the Boston-based cosmetic dermatology practice that employed Catherine M. DiGiorgio, MD, MS, was sold to a private equity firm a few years ago, she found herself at a crossroads: Stay and work for a large corporation, or open a solo practice?

She opted to start her own practice in Boston, “because I didn’t want to work for a large corporation, and I want to provide the best care for my patients in a more intimate manner,” Dr. DiGiorgio, a board-certified laser and cosmetic dermatologist, said at the annual Masters of Aesthetics Symposium.

Dr. DiGiorgio

The decision also tested her mettle. “I spoke to several colleagues and friends, and I was terrified,” she said. “I was like: ‘I don’t even know where to start.’ ”

On the heels of opening a new office in a matter of weeks, she offered the following tips and questions to consider when launching a solo dermatology practice:

Select a location. “That’s your first decision,” she said. “Where in the city are you going to open? Are you going to a new city, or are you moving back home? Don’t be afraid to start from scratch, and don’t be afraid to start a [solo] practice if you already have a patient base.”

Will you lease or purchase your space? After she secured a bank loan, Dr. DiGiorgio chose to lease the space for her new practice, “because you can kind of see where things go, get all the kinks out and figure out how to build things in a space that you don’t own. Then, when you’re ready and you have grown, you can invest more into your practice.”

Will you accept insurance? She built her practice around the direct specialty care model, which emphasizes the patient-physician relationship and removes third-party payors. “It’s not a concierge practice, but it’s a transparent, reasonable fee schedule for medical dermatology,” she explained. “I’ve done 100% cosmetics for about 5 years now, [but] I do medical dermatology for a fee. On my website I have a full price list on how much a full skin check is, [and] how much biopsies are. It’s completely transparent. Patients can submit to their insurance for reimbursement, but we don’t guarantee that they’re going to be reimbursed.”

Where will your patients come from? Will you advertise? Do you have physicians in the area who will refer to you if you’re a board-certified dermatologist? She emphasized the importance of “learning how to present yourself” on a website dedicated to your own practice. “Instagram, Facebook, and social media are great, but you don’t own those pages,” noted Dr. DiGiorgio, who served as the program cochair of the 2023 annual meeting of the American Society for Laser Medicine and Surgery and was recently elected to serve on the board of directors for the American Society for Dermatology Surgery. “You don’t own one of those pictures that are posted on your social media page. They can disappear in a second. If that happens, how are people going to find you?”

Are you going to hire more physicians in the future? That will influence the size of the new office and the floor plan.

Lawyer up. Hiring a health care attorney can “help you navigate transitioning from whatever position you’re in to opening up your own practice, as well as setting up the regulatory paperwork necessary for your new practice. You’ll also need a real estate attorney to help once you have selected a place, to help you navigate through that process,” she said, such as figuring out if the elevator in the building meets the Americans With Disabilities Act (ADA) requirements.

Create a mission statement. That way, “you know why you’re doing this, and it stays with you as you’re getting through the hard roadblocks.”

Find an architect, contractor, or designer. “If you’re building out a space from scratch, you’re going to need an architect,” she said. “Along with that architect will come a full-on contracting firm. I ended up hiring everyone individually, because I’m trying to spend as little money as possible.” She also hired a designer to help select furnishings and create the office atmosphere.

Secure a building permit ASAP. “It’s almost better to have the city permit before you sign the lease, because the permits can take a year, and you don’t want to pay rent on an empty space for a year if you don’t have a permit or if there are other hoops to go through,” Dr. DiGiorgio said.

Find an agent to help you set up medical malpractice insurance, liability insurance, and worker’s compensation insurance. “Make sure you read all the paperwork, because it can be very intricate,” she said.

Find an accountant. That person can help set up a bookkeeping process.

What equipment and devices will you need? That depends largely on the patient population a physician serves. Dr. DiGiorgio noted that eligible small businesses may take a tax credit of up to $5,000 per year for accommodations made to comply with the ADA. “That’s a nice feature, so that you can purchase ADA compliant items like a larger exam chair and custom reception areas.”

Dr. DiGiorgio reported having no relevant disclosures.

COPENHAGEN – Giving patients with Parkinson’s disease and constipation a probiotic for 3 months improved not only their gut microbiome but also nonmotor symptoms such as sleep, fatigue, and constipation, results of a new randomized trial show.

Participants taking the probiotic also saw a reduced delay in “time to on” of treatment with levodopa, thus reducing the delay until effectiveness of the treatment, said study presenter Valentina Leta, MD, PhD, department of neurosciences, King’s College London Institute of Psychiatry, Psychology and Neuroscience.

Dr. Leta presented the findings at the International Congress of Parkinson’s Disease and Movement Disorders.

“Virtually every person with Parkinson’s might have some degree of gastrointestinal dysfunction, and virtually the entire tract might be affected, from the mouth to the rectum,” Dr. Leta told attendees of the congress.

A number of different mechanisms have been associated with this gastrointestinal dysfunction, she noted, including proinflammatory changes in the gut microbiota, so a modulatory intervention “could be a therapeutic strategy for Parkinson’s disease.”

However, “despite numerous preclinical studies showing potential beneficial effects on a variety of pathological mechanisms involved in Parkinson’s disease, the clinical evidence is limited ... to the treatment of constipation,” she explained.

The team therefore conducted a multicenter, randomized, double-blind, placebo-controlled trial, in which patients with both Parkinson’s disease and constipation, based on the Rome IV criteria, were randomly assigned to receive a probiotic or placebo for 3 months.

The probiotic used was a liquid formulation (Symprove) and contained four strains: Lacticaseibacillus rhamnosus, Enterococcus faecium, Lactobacillus acidophilus, and Lactiplantibacillus plantarum.

A total of 74 patients were randomly assigned to the two study arms. The two groups were well matched for sociodemographics, Parkinson’s disease, and constipation-related characteristics, Dr. Leta reported, and only 3 patients in each arm discontinued the study. The probiotic intervention had a “good tolerability and safety profile, with a similar number of adverse events between the two groups, and no serious adverse events.”
 

Increase in healthy bacteria

The study met its primary outcome of changes in gut microbiome at the end of the 12-week intervention, as measured on shallow shotgun sequencing.

The probiotic was associated with a “statistically significant increase of the abundance of bacteria which are known to have beneficial health related properties, such as Odoribacteraceae,” Dr. Leta said.

This bacterium is “known to be reduced in people with Parkinson’s disease,” she explained, “and is involved in the production of short-chain fatty acids, which are known to have beneficial health-related properties.”

The secondary endpoint of the study included changes in motor and nonmotor symptoms, and the probiotic was associated with a significant improvement in the “time to on” with levodopa treatment, shortening this period from an average of 31.43 minutes at baseline to 23.95 minutes at the postintervention assessment (P < .027).

There was also a significant improvement in the Non-Motor Symptoms Scale (NMSS) score between baseline and the postintervention assessment in patients given the probiotic, from 70.71 to 61.34 (P = .005).

This, Dr. Leta observed, was “driven by improvements in the sleep, fatigue, and gastrointestinal domains.”

No such significant improvements were observed in the placebo arm.
 

Probiotics ‘hot topic’ among patients

Claudia Trenkwalder, MD, full professor of neurology at University Medical Center Goettingen (Germany), said in an interview that the use of probiotics is a “hot topic in Parkinson’s disease research, especially among patients.”

Dr. Trenkwalder, who was not involved in the study, noted that Lactobacillus strains “are established in Parkinson’s disease constipation treatment, with randomized controlled trials showing a significant improvement in constipation.

“Therefore, this is a useful treatment. The question here is: Do we have additional effects that can be measured in the microbiome and in clinical symptomatology?”

The trial showed that the probiotic studied “did alter the microbiome and did improve the constipation,” said Dr. Trenkwalder; however, the current data cannot prove whether the probiotic influenced the symptoms of Parkinson’s disease because the improvement in NMSS scores “is driven by the improvement in constipation.”

This, she argued, could have resulted in better absorption of levodopa.

A dietitian in the audience agreed. She asked whether the probiotic was doing anything “besides improving constipation,” adding that the resulting increased ability to absorb levodopa is also “going to help your sleep.”
 

Beyond constipation?

Dr. Leta replied that “we can assume that there is a link between the reduction in the ‘time to on’ and the improvement in constipation. We are doing some analyses in terms of levodopa pharmacokinetics to really understand the mechanisms behind this result.”

Although the improvement in constipation is “one of the possible hypotheses for the improvement in ‘time to on,’” she continued, “there is a more speculative one” in which the probiotics are modulating inflammatory parameters that could contribute to the improvement in sleep.

Veronica Bruno, MD, MPH, assistant professor in the department of clinical neurosciences at the University of Calgary (Alta.), commented in a press release that there has been “increasing interest” in examining the relationship between gut dysbiosis and the “gut-brain axis” in Parkinson’s disease.

The current study “stands out as a significant contribution to this area of study,” she said.

“While the implications of the observed changes in gut microbiota remain a captivating realm for further investigation, a particularly noteworthy finding revolves around the reduction in the ‘time to on’ observed within the active treatment group.”

Dr. Bruno said that shortening of the time to on “holds promise for substantial enhancements in patients’ lives” by reducing “difficult ‘off’ intervals and enhancing overall well-being.”

The study was funded by the UK National Institute for Health Research Mental Health Biomedical Research Centre and Dementia Unit at South London and Maudsley NHS Foundation Trust, and King’s College London. No relevant financial relationships were declared.

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

COPENHAGEN – Giving patients with Parkinson’s disease and constipation a probiotic for 3 months improved not only their gut microbiome but also nonmotor symptoms such as sleep, fatigue, and constipation, results of a new randomized trial show.

Participants taking the probiotic also saw a reduced delay in “time to on” of treatment with levodopa, thus reducing the delay until effectiveness of the treatment, said study presenter Valentina Leta, MD, PhD, department of neurosciences, King’s College London Institute of Psychiatry, Psychology and Neuroscience.

Dr. Leta presented the findings at the International Congress of Parkinson’s Disease and Movement Disorders.

“Virtually every person with Parkinson’s might have some degree of gastrointestinal dysfunction, and virtually the entire tract might be affected, from the mouth to the rectum,” Dr. Leta told attendees of the congress.

A number of different mechanisms have been associated with this gastrointestinal dysfunction, she noted, including proinflammatory changes in the gut microbiota, so a modulatory intervention “could be a therapeutic strategy for Parkinson’s disease.”

However, “despite numerous preclinical studies showing potential beneficial effects on a variety of pathological mechanisms involved in Parkinson’s disease, the clinical evidence is limited ... to the treatment of constipation,” she explained.

The team therefore conducted a multicenter, randomized, double-blind, placebo-controlled trial, in which patients with both Parkinson’s disease and constipation, based on the Rome IV criteria, were randomly assigned to receive a probiotic or placebo for 3 months.

The probiotic used was a liquid formulation (Symprove) and contained four strains: Lacticaseibacillus rhamnosus, Enterococcus faecium, Lactobacillus acidophilus, and Lactiplantibacillus plantarum.

A total of 74 patients were randomly assigned to the two study arms. The two groups were well matched for sociodemographics, Parkinson’s disease, and constipation-related characteristics, Dr. Leta reported, and only 3 patients in each arm discontinued the study. The probiotic intervention had a “good tolerability and safety profile, with a similar number of adverse events between the two groups, and no serious adverse events.”
 

Increase in healthy bacteria

The study met its primary outcome of changes in gut microbiome at the end of the 12-week intervention, as measured on shallow shotgun sequencing.

The probiotic was associated with a “statistically significant increase of the abundance of bacteria which are known to have beneficial health related properties, such as Odoribacteraceae,” Dr. Leta said.

This bacterium is “known to be reduced in people with Parkinson’s disease,” she explained, “and is involved in the production of short-chain fatty acids, which are known to have beneficial health-related properties.”

The secondary endpoint of the study included changes in motor and nonmotor symptoms, and the probiotic was associated with a significant improvement in the “time to on” with levodopa treatment, shortening this period from an average of 31.43 minutes at baseline to 23.95 minutes at the postintervention assessment (P < .027).

There was also a significant improvement in the Non-Motor Symptoms Scale (NMSS) score between baseline and the postintervention assessment in patients given the probiotic, from 70.71 to 61.34 (P = .005).

This, Dr. Leta observed, was “driven by improvements in the sleep, fatigue, and gastrointestinal domains.”

No such significant improvements were observed in the placebo arm.
 

Probiotics ‘hot topic’ among patients

Claudia Trenkwalder, MD, full professor of neurology at University Medical Center Goettingen (Germany), said in an interview that the use of probiotics is a “hot topic in Parkinson’s disease research, especially among patients.”

Dr. Trenkwalder, who was not involved in the study, noted that Lactobacillus strains “are established in Parkinson’s disease constipation treatment, with randomized controlled trials showing a significant improvement in constipation.

“Therefore, this is a useful treatment. The question here is: Do we have additional effects that can be measured in the microbiome and in clinical symptomatology?”

The trial showed that the probiotic studied “did alter the microbiome and did improve the constipation,” said Dr. Trenkwalder; however, the current data cannot prove whether the probiotic influenced the symptoms of Parkinson’s disease because the improvement in NMSS scores “is driven by the improvement in constipation.”

This, she argued, could have resulted in better absorption of levodopa.

A dietitian in the audience agreed. She asked whether the probiotic was doing anything “besides improving constipation,” adding that the resulting increased ability to absorb levodopa is also “going to help your sleep.”
 

Beyond constipation?

Dr. Leta replied that “we can assume that there is a link between the reduction in the ‘time to on’ and the improvement in constipation. We are doing some analyses in terms of levodopa pharmacokinetics to really understand the mechanisms behind this result.”

Although the improvement in constipation is “one of the possible hypotheses for the improvement in ‘time to on,’” she continued, “there is a more speculative one” in which the probiotics are modulating inflammatory parameters that could contribute to the improvement in sleep.

Veronica Bruno, MD, MPH, assistant professor in the department of clinical neurosciences at the University of Calgary (Alta.), commented in a press release that there has been “increasing interest” in examining the relationship between gut dysbiosis and the “gut-brain axis” in Parkinson’s disease.

The current study “stands out as a significant contribution to this area of study,” she said.

“While the implications of the observed changes in gut microbiota remain a captivating realm for further investigation, a particularly noteworthy finding revolves around the reduction in the ‘time to on’ observed within the active treatment group.”

Dr. Bruno said that shortening of the time to on “holds promise for substantial enhancements in patients’ lives” by reducing “difficult ‘off’ intervals and enhancing overall well-being.”

The study was funded by the UK National Institute for Health Research Mental Health Biomedical Research Centre and Dementia Unit at South London and Maudsley NHS Foundation Trust, and King’s College London. No relevant financial relationships were declared.

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

COPENHAGEN – Giving patients with Parkinson’s disease and constipation a probiotic for 3 months improved not only their gut microbiome but also nonmotor symptoms such as sleep, fatigue, and constipation, results of a new randomized trial show.

Participants taking the probiotic also saw a reduced delay in “time to on” of treatment with levodopa, thus reducing the delay until effectiveness of the treatment, said study presenter Valentina Leta, MD, PhD, department of neurosciences, King’s College London Institute of Psychiatry, Psychology and Neuroscience.

Dr. Leta presented the findings at the International Congress of Parkinson’s Disease and Movement Disorders.

“Virtually every person with Parkinson’s might have some degree of gastrointestinal dysfunction, and virtually the entire tract might be affected, from the mouth to the rectum,” Dr. Leta told attendees of the congress.

A number of different mechanisms have been associated with this gastrointestinal dysfunction, she noted, including proinflammatory changes in the gut microbiota, so a modulatory intervention “could be a therapeutic strategy for Parkinson’s disease.”

However, “despite numerous preclinical studies showing potential beneficial effects on a variety of pathological mechanisms involved in Parkinson’s disease, the clinical evidence is limited ... to the treatment of constipation,” she explained.

The team therefore conducted a multicenter, randomized, double-blind, placebo-controlled trial, in which patients with both Parkinson’s disease and constipation, based on the Rome IV criteria, were randomly assigned to receive a probiotic or placebo for 3 months.

The probiotic used was a liquid formulation (Symprove) and contained four strains: Lacticaseibacillus rhamnosus, Enterococcus faecium, Lactobacillus acidophilus, and Lactiplantibacillus plantarum.

A total of 74 patients were randomly assigned to the two study arms. The two groups were well matched for sociodemographics, Parkinson’s disease, and constipation-related characteristics, Dr. Leta reported, and only 3 patients in each arm discontinued the study. The probiotic intervention had a “good tolerability and safety profile, with a similar number of adverse events between the two groups, and no serious adverse events.”
 

Increase in healthy bacteria

The study met its primary outcome of changes in gut microbiome at the end of the 12-week intervention, as measured on shallow shotgun sequencing.

The probiotic was associated with a “statistically significant increase of the abundance of bacteria which are known to have beneficial health related properties, such as Odoribacteraceae,” Dr. Leta said.

This bacterium is “known to be reduced in people with Parkinson’s disease,” she explained, “and is involved in the production of short-chain fatty acids, which are known to have beneficial health-related properties.”

The secondary endpoint of the study included changes in motor and nonmotor symptoms, and the probiotic was associated with a significant improvement in the “time to on” with levodopa treatment, shortening this period from an average of 31.43 minutes at baseline to 23.95 minutes at the postintervention assessment (P < .027).

There was also a significant improvement in the Non-Motor Symptoms Scale (NMSS) score between baseline and the postintervention assessment in patients given the probiotic, from 70.71 to 61.34 (P = .005).

This, Dr. Leta observed, was “driven by improvements in the sleep, fatigue, and gastrointestinal domains.”

No such significant improvements were observed in the placebo arm.
 

Probiotics ‘hot topic’ among patients

Claudia Trenkwalder, MD, full professor of neurology at University Medical Center Goettingen (Germany), said in an interview that the use of probiotics is a “hot topic in Parkinson’s disease research, especially among patients.”

Dr. Trenkwalder, who was not involved in the study, noted that Lactobacillus strains “are established in Parkinson’s disease constipation treatment, with randomized controlled trials showing a significant improvement in constipation.

“Therefore, this is a useful treatment. The question here is: Do we have additional effects that can be measured in the microbiome and in clinical symptomatology?”

The trial showed that the probiotic studied “did alter the microbiome and did improve the constipation,” said Dr. Trenkwalder; however, the current data cannot prove whether the probiotic influenced the symptoms of Parkinson’s disease because the improvement in NMSS scores “is driven by the improvement in constipation.”

This, she argued, could have resulted in better absorption of levodopa.

A dietitian in the audience agreed. She asked whether the probiotic was doing anything “besides improving constipation,” adding that the resulting increased ability to absorb levodopa is also “going to help your sleep.”
 

Beyond constipation?

Dr. Leta replied that “we can assume that there is a link between the reduction in the ‘time to on’ and the improvement in constipation. We are doing some analyses in terms of levodopa pharmacokinetics to really understand the mechanisms behind this result.”

Although the improvement in constipation is “one of the possible hypotheses for the improvement in ‘time to on,’” she continued, “there is a more speculative one” in which the probiotics are modulating inflammatory parameters that could contribute to the improvement in sleep.

Veronica Bruno, MD, MPH, assistant professor in the department of clinical neurosciences at the University of Calgary (Alta.), commented in a press release that there has been “increasing interest” in examining the relationship between gut dysbiosis and the “gut-brain axis” in Parkinson’s disease.

The current study “stands out as a significant contribution to this area of study,” she said.

“While the implications of the observed changes in gut microbiota remain a captivating realm for further investigation, a particularly noteworthy finding revolves around the reduction in the ‘time to on’ observed within the active treatment group.”

Dr. Bruno said that shortening of the time to on “holds promise for substantial enhancements in patients’ lives” by reducing “difficult ‘off’ intervals and enhancing overall well-being.”

The study was funded by the UK National Institute for Health Research Mental Health Biomedical Research Centre and Dementia Unit at South London and Maudsley NHS Foundation Trust, and King’s College London. No relevant financial relationships were declared.

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

The timing of complete revascularization (CR) in patients with acute ST-elevation myocardial infarction (STEMI) and multivessel disease (MVD) may make little clinical difference.

The conclusion comes from a randomized outcomes trial of 840 patients that compared prompt same-session CR with a staged procedure carried out weeks later.

That CR is a worthy goal in such cases is largely settled, unlike the question of when to pursue revascularization of nonculprit lesions for best results. So the timing varies in practice, often depending on the patient’s clinical stability, risk status, or practical issues like cath lab resources or personnel.

The new trial, MULTISTARS-AMI, supports that kind of flexibility as safe in practice. Immediate, same-session CR led to a 48% drop in risk for a broad composite primary endpoint at 1 year, compared with staged CR an average of 37 days later. The finding was significant for noninferiority in the study’s primary analysis and secondarily, was significant for superiority (P < .001 in both cases).

The composite endpoint included death from any cause, MI, stroke, unplanned ischemia-driven revascularization, or heart failure (HF) hospitalization.

CR’s immediate effect on outcomes was numerically pronounced, but because it was prespecified as a noninferiority trial, MULTISTARS-AMI could show only that the strategy is comparable to staged CR, emphasized Barbara E. Stähli, MD, MPH, MBA, at a press conference.

Still, it appears to be the first trial of its kind to show that operators and patients can safely choose either percutaneous coronary intervention (PCI) approach and attain similar outcomes, said Dr. Stähli, University Hospital Zurich, MULTISTARS-AMI’s principal investigator.

Not only were the two approaches similar with respect to safety, she noted, but immediate CR seemed to require less use of contrast agent and fluoroscopy. “And you have only one procedure, so there’s only one arterial puncture.”

Dr. Stähli formally presented MULTISTARS-AMI at the annual congress of the European Society of Cardiology, held in Amsterdam. She is also lead author on its publication in the New England Journal of Medicine.

After her presentation, invited discussant Robert A. Byrne, PhD, MD, MB, BCh, said that the trial’s central message is that STEMI patients with MVD having primary PCI “should undergo complete revascularization within the first 45 days, with the timing of the non–infarct-related artery procedure individualized according to clinical risk and logistical considerations.”

Still, the trial “provides evidence, but not strong evidence, of benefits with routine immediate PCI during the index procedure as compared with staged outpatient PCI,” said Dr. Byrne, Mater Private Hospital and RCSI University of Medicine and Health Sciences, Dublin.

MULTISTARS-AMI randomly assigned patients at 37 European sites to undergo same-session CR (418 patients) or CR staged 19-45 days later (422 patients).

Rates for the primary endpoint at 1 year were 8.5% and 16.3%, respectively, for a risk ratio of 0.52 (95% confidence interval, 0.38-0.72). The difference was driven by fewer instances of nonfatal MI, 0.36 (95% CI, 0.16-0.80), and unplanned ischemia-driven revascularization, 0.42 (95% CI, 0.24-0.74), in the immediate-CR group.
 

The wee hours

Sunil V. Rao, MD, director of interventional cardiology at NYU Langone Health System, New York, said that, in general at his center, patients who are stable with a good primary PCI outcome and whose lesions aren’t very high risk are often discharged to return later for the staged CR procedure.

But after the new insights from MULTISTARS-AMI, Dr. Rao, who is not connected to the study, said in an interview that immediate same-session CR is indeed likely preferable to staged CR performed weeks later.

Same-session CR, however, may not always be practical or wise, he observed. For example, some patients with STEMI can be pretty sick with MVD that involves very complex lesions that might be better handled later.

“The wee hours of the night may not be the best time to tackle such complex lesions,” Dr. Rao observed. If confronted with, for example, a bifurcation that requires a complex procedure, “2 o’clock in the morning is probably not the best time to address something like that.”

So the trial’s more realistic translational message, he proposed, may be to perform CR after the primary PCI but during the same hospitalization, “unless there are some real mitigating circumstances.” 

The trial was supported by Boston Scientific. Dr. Stähli had no disclosures. Dr. Byrne discloses research funding to his institution from Abbott Vascular, Translumina, Biosensors, and Boston Scientific. Dr. Rao had no relevant disclosures.

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

The timing of complete revascularization (CR) in patients with acute ST-elevation myocardial infarction (STEMI) and multivessel disease (MVD) may make little clinical difference.

The conclusion comes from a randomized outcomes trial of 840 patients that compared prompt same-session CR with a staged procedure carried out weeks later.

That CR is a worthy goal in such cases is largely settled, unlike the question of when to pursue revascularization of nonculprit lesions for best results. So the timing varies in practice, often depending on the patient’s clinical stability, risk status, or practical issues like cath lab resources or personnel.

The new trial, MULTISTARS-AMI, supports that kind of flexibility as safe in practice. Immediate, same-session CR led to a 48% drop in risk for a broad composite primary endpoint at 1 year, compared with staged CR an average of 37 days later. The finding was significant for noninferiority in the study’s primary analysis and secondarily, was significant for superiority (P < .001 in both cases).

The composite endpoint included death from any cause, MI, stroke, unplanned ischemia-driven revascularization, or heart failure (HF) hospitalization.

CR’s immediate effect on outcomes was numerically pronounced, but because it was prespecified as a noninferiority trial, MULTISTARS-AMI could show only that the strategy is comparable to staged CR, emphasized Barbara E. Stähli, MD, MPH, MBA, at a press conference.

Still, it appears to be the first trial of its kind to show that operators and patients can safely choose either percutaneous coronary intervention (PCI) approach and attain similar outcomes, said Dr. Stähli, University Hospital Zurich, MULTISTARS-AMI’s principal investigator.

Not only were the two approaches similar with respect to safety, she noted, but immediate CR seemed to require less use of contrast agent and fluoroscopy. “And you have only one procedure, so there’s only one arterial puncture.”

Dr. Stähli formally presented MULTISTARS-AMI at the annual congress of the European Society of Cardiology, held in Amsterdam. She is also lead author on its publication in the New England Journal of Medicine.

After her presentation, invited discussant Robert A. Byrne, PhD, MD, MB, BCh, said that the trial’s central message is that STEMI patients with MVD having primary PCI “should undergo complete revascularization within the first 45 days, with the timing of the non–infarct-related artery procedure individualized according to clinical risk and logistical considerations.”

Still, the trial “provides evidence, but not strong evidence, of benefits with routine immediate PCI during the index procedure as compared with staged outpatient PCI,” said Dr. Byrne, Mater Private Hospital and RCSI University of Medicine and Health Sciences, Dublin.

MULTISTARS-AMI randomly assigned patients at 37 European sites to undergo same-session CR (418 patients) or CR staged 19-45 days later (422 patients).

Rates for the primary endpoint at 1 year were 8.5% and 16.3%, respectively, for a risk ratio of 0.52 (95% confidence interval, 0.38-0.72). The difference was driven by fewer instances of nonfatal MI, 0.36 (95% CI, 0.16-0.80), and unplanned ischemia-driven revascularization, 0.42 (95% CI, 0.24-0.74), in the immediate-CR group.
 

The wee hours

Sunil V. Rao, MD, director of interventional cardiology at NYU Langone Health System, New York, said that, in general at his center, patients who are stable with a good primary PCI outcome and whose lesions aren’t very high risk are often discharged to return later for the staged CR procedure.

But after the new insights from MULTISTARS-AMI, Dr. Rao, who is not connected to the study, said in an interview that immediate same-session CR is indeed likely preferable to staged CR performed weeks later.

Same-session CR, however, may not always be practical or wise, he observed. For example, some patients with STEMI can be pretty sick with MVD that involves very complex lesions that might be better handled later.

“The wee hours of the night may not be the best time to tackle such complex lesions,” Dr. Rao observed. If confronted with, for example, a bifurcation that requires a complex procedure, “2 o’clock in the morning is probably not the best time to address something like that.”

So the trial’s more realistic translational message, he proposed, may be to perform CR after the primary PCI but during the same hospitalization, “unless there are some real mitigating circumstances.” 

The trial was supported by Boston Scientific. Dr. Stähli had no disclosures. Dr. Byrne discloses research funding to his institution from Abbott Vascular, Translumina, Biosensors, and Boston Scientific. Dr. Rao had no relevant disclosures.

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

The timing of complete revascularization (CR) in patients with acute ST-elevation myocardial infarction (STEMI) and multivessel disease (MVD) may make little clinical difference.

The conclusion comes from a randomized outcomes trial of 840 patients that compared prompt same-session CR with a staged procedure carried out weeks later.

That CR is a worthy goal in such cases is largely settled, unlike the question of when to pursue revascularization of nonculprit lesions for best results. So the timing varies in practice, often depending on the patient’s clinical stability, risk status, or practical issues like cath lab resources or personnel.

The new trial, MULTISTARS-AMI, supports that kind of flexibility as safe in practice. Immediate, same-session CR led to a 48% drop in risk for a broad composite primary endpoint at 1 year, compared with staged CR an average of 37 days later. The finding was significant for noninferiority in the study’s primary analysis and secondarily, was significant for superiority (P < .001 in both cases).

The composite endpoint included death from any cause, MI, stroke, unplanned ischemia-driven revascularization, or heart failure (HF) hospitalization.

CR’s immediate effect on outcomes was numerically pronounced, but because it was prespecified as a noninferiority trial, MULTISTARS-AMI could show only that the strategy is comparable to staged CR, emphasized Barbara E. Stähli, MD, MPH, MBA, at a press conference.

Still, it appears to be the first trial of its kind to show that operators and patients can safely choose either percutaneous coronary intervention (PCI) approach and attain similar outcomes, said Dr. Stähli, University Hospital Zurich, MULTISTARS-AMI’s principal investigator.

Not only were the two approaches similar with respect to safety, she noted, but immediate CR seemed to require less use of contrast agent and fluoroscopy. “And you have only one procedure, so there’s only one arterial puncture.”

Dr. Stähli formally presented MULTISTARS-AMI at the annual congress of the European Society of Cardiology, held in Amsterdam. She is also lead author on its publication in the New England Journal of Medicine.

After her presentation, invited discussant Robert A. Byrne, PhD, MD, MB, BCh, said that the trial’s central message is that STEMI patients with MVD having primary PCI “should undergo complete revascularization within the first 45 days, with the timing of the non–infarct-related artery procedure individualized according to clinical risk and logistical considerations.”

Still, the trial “provides evidence, but not strong evidence, of benefits with routine immediate PCI during the index procedure as compared with staged outpatient PCI,” said Dr. Byrne, Mater Private Hospital and RCSI University of Medicine and Health Sciences, Dublin.

MULTISTARS-AMI randomly assigned patients at 37 European sites to undergo same-session CR (418 patients) or CR staged 19-45 days later (422 patients).

Rates for the primary endpoint at 1 year were 8.5% and 16.3%, respectively, for a risk ratio of 0.52 (95% confidence interval, 0.38-0.72). The difference was driven by fewer instances of nonfatal MI, 0.36 (95% CI, 0.16-0.80), and unplanned ischemia-driven revascularization, 0.42 (95% CI, 0.24-0.74), in the immediate-CR group.
 

The wee hours

Sunil V. Rao, MD, director of interventional cardiology at NYU Langone Health System, New York, said that, in general at his center, patients who are stable with a good primary PCI outcome and whose lesions aren’t very high risk are often discharged to return later for the staged CR procedure.

But after the new insights from MULTISTARS-AMI, Dr. Rao, who is not connected to the study, said in an interview that immediate same-session CR is indeed likely preferable to staged CR performed weeks later.

Same-session CR, however, may not always be practical or wise, he observed. For example, some patients with STEMI can be pretty sick with MVD that involves very complex lesions that might be better handled later.

“The wee hours of the night may not be the best time to tackle such complex lesions,” Dr. Rao observed. If confronted with, for example, a bifurcation that requires a complex procedure, “2 o’clock in the morning is probably not the best time to address something like that.”

So the trial’s more realistic translational message, he proposed, may be to perform CR after the primary PCI but during the same hospitalization, “unless there are some real mitigating circumstances.” 

The trial was supported by Boston Scientific. Dr. Stähli had no disclosures. Dr. Byrne discloses research funding to his institution from Abbott Vascular, Translumina, Biosensors, and Boston Scientific. Dr. Rao had no relevant disclosures.

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

AMSTERDAM – A simple, low-cost 5-day course of dietary inorganic nitrate has shown apparent overwhelming benefit in preventing contrast-induced nephropathy (CIN) and reducing subsequent renal and cardiovascular outcomes.

In the NITRATE-CIN Study, non-ST segment elevation myocardial infarction acute coronary syndrome (ACS) patients at risk of renal injury from coronary angiography who received dietary inorganic nitrates had a 70% reduction in CIN compared with those given placebo.

The nitrate group also showed an impressive reduction in periprocedural myocardial infarction (MI) and improved renal function at 3 months, as well as a halving of major adverse cardiovascular events and major adverse kidney events at 1 year.

The trial was presented by Dan Jones, MD, Barts Health NHS Trust, London, at the annual congress of the European Society of Cardiology.

“Currently, aside from intravenous hydration, there is no proven treatment that reduces contrast-induced nephropathy. We feel that dietary inorganic nitrate shows huge promise in this study, and these findings could have important implications in reducing this serious complication of coronary angiography,” Dr. Jones concluded.

He explained that the product used was a formulation of dietary inorganic nitrates given as potassium nitrate capsules, which the study investigators produced specifically for this trial.

At this point, “the only way to get inorganic nitrate is in the diet – specifically by consuming beetroot juice or green leafy vegetables such as spinach and rocket. From a clinician perspective, while these results suggest this is an effective therapy and has great potential, it is not currently possible to prescribe the medication we used in our study, although we are working on producing a commercial product,” he said in an interview.

However, Dr. Jones noted that it is possible to buy beetroot shots, which contain 7 mmol of potassium nitrate in each shot, from health food shops and websites, and two such shots per day for 5 days would give a dose similar to that used in this study, starting the day before angiography.

“While we need a larger multicenter study to confirm these results, studies so far suggest no signal at all that there is any harm in this approach, and there could be a great deal of benefit in taking a couple of beetroot shots prior to and for a few days after an angiogram,” he said.
 

Dietary nitrates “make sense”

Designated discussant of the NITRATE-CIN trial at the ESC Hotline session, Roxanna Mehran, MD, Icahn School of Medicine at Mount Sinai, New York, said the study was well designed, and the “interesting and plausible” hypothesis to raise nitric oxide levels by dietary nitrates “makes sense.”

On the main findings of a major significant 50% reduction in acute kidney injury, Dr. Mehran said, “It is difficult to imagine such a reduction is possible.”

She pointed out that the large reduction in major adverse cardiac events and major adverse kidney events at 1 year also suggests that there is a sustained benefit in protecting the kidney.

“We’re all going to get on beet juice after this,” she quipped.

Still, Dr. Mehran questioned whether the results were “too good to be true,” adding that a larger trial actually powered for longer term outcome events is needed, as well as a better understanding of whether CIN has a causative role in mortality.

Responding to questions about whether such a large effect could actually be achieved with dietary nitrates, Dr. Jones said he thought there would definitely be some benefits, but maybe not quite as large as those seen in this study.

“From our pilot data we thought nitrate may be effective in preventing CIN,” he said in an interview. “We recruited a higher risk group than we thought, which is why the control event rates were higher than we expected, but the acute kidney injury reduction is roughly what we had estimated, and makes sense biologically.”

Dr. Jones acknowledged that the large reductions in long-term major adverse cardiovascular and kidney events were unexpected.

“The trial was not powered to see reductions in these outcomes, so we need to see if those event reductions can be replicated in larger multicenter trials,” he said. “But this was a double-blind placebo-controlled trial so in this trial the effects are real, and I think the effect size in this trial is too large for there not to be a beneficial effect.

“But I’m not so sure that we would see the same magnitude of effect when we have a larger study with tighter confidence intervals but perhaps a 20%-25% reduction in cardiovascular and kidney may be more realistic, which would still be amazing for such an easy and cost-effective intervention,” Dr. Jones added.

A larger trial is now being planned.

The researchers are also working on the development of a commercial form of dietary inorganic nitrate that would be needed for larger multicenter studies and would then be generally available. “We want this to be a low-cost product that would be available to all,” Dr. Jones said.

He noted that other studies have shown that dietary inorganic nitrates in the form of beetroot juice lower blood pressure; there are suggestions it may also lower cholesterol and prevent stent restenosis, and athletes sometimes take it to increase their aerobic capacity.

“There appears to be many benefits of dietary nitrates, and the one thing we can do at this time is to encourage people to increase their dietary nitrate consumption by eating large quantities of green leafy vegetables and beetroot,” Dr. Jones said.
 

Replacing lost nitric oxide

In his presentation, Dr. Jones noted that CIN is a serious complication after coronary angiography and is associated with longer hospital stays, worse long-term kidney function, and increased risk of MI and death.

The incidence varies depending on patient risk and definitions used, but it can affect up to 50% of high-risk ACS patients – older patients and/or those with heart failure, chronic kidney disease, or diabetes.

“We don’t really understand the mechanisms that cause CIN, but multiple proposed mechanisms exist, and we know from previous studies that a deficiency of nitric oxide is crucial to the development of CIN,” he explained. “We also know that [nitric oxide] is crucial for normal renal hemostasis. Therefore, a potential therapeutic target to prevent CIN would be to replace this lost nitric oxide.”

The inorganic nitrate evaluated in this trial is found in the diet, is produced endogenously, and is different from medicinally synthesized organic nitrates such as isosorbide mononitrate, he said.

“Isosorbide mononitrate/dinitrate tablets contain organic nitrates and while they are good for angina, we know that they do not have the same beneficial effects on the sustained generation of nitric oxide as inorganic nitrates,” Dr. Jones added.
 

NITRATE-CIN study

NITRATE-CIN was a double-blind, randomized, placebo-controlled trial conducted at Queen Mary University of London and St. Bartholomew’s Hospital in London, which tested the effectiveness of inorganic nitrate in preventing contrast-induced nephropathy in 640 patients with non-ST elevation ACS referred for invasive coronary angiography.

To be eligible for the trial, patients had to be at risk of contrast-induced nephropathy with an estimated glomerular filtration rate (eGFR) less than 60 mL/min per 1.73 m² or have two of the following significant risk factors: diabetes, liver failure, over 70 years of age, exposure to contrast within 7 days, heart failure, or on concomitant renally acting drugs.

Patients were randomly assigned to a formulation of potassium nitrate (12 mmol/744 mg nitrate) per day given as capsules for a 5-day course with the first dose administered prior to angiography or to a control group that received potassium chloride with a matched potassium concentration.

The patient population had a mean age of 71 years, 73% were male, 75% were White, 46% had diabetes, and 56% had chronic kidney disease. There was a 13% loss to follow-up, which was attributed to the COVID pandemic.

The amount of contrast administration was 180 mL in the placebo and 170 mL in the nitrate arm, with 50% of patients undergoing some sort of revascularization.

The primary endpoint was the incidence of CIN as defined by KDIGO criteria – a series of stages of acute kidney injury defined by changes in serum creatinine within 72 hours and up to 1 week.

Results showed that this primary CIN endpoint was reduced significantly from 30% in the placebo arm to 9.1% in the nitrate group, a 70% relative risk reduction (P < .0001). The majority (90%) of this CIN was stage 1, but 10% was stage 2.

Consistent results were seen when an alternative definition of CIN (Mehran) was used, although the rates in both arms were lower than when the KDIGO definition was used.

The benefit was seen across prespecified subgroups including diabetes status, troponin positivity, and Mehran risk. But the benefit seemed to be attenuated in patients on preexisting organic nitrate therapy, although the numbers in these groups were too small to draw definitive conclusions.

As would be expected, there were significant elevations in both systemic nitrate and nitrite levels both up to 72 hours after the procedure, which was consistent with the 5-day course. This was associated with reductions in systolic and diastolic blood pressure, but not associated with any adverse events, Dr. Jones reported.

Rates of procedural MI, a prespecified secondary endpoint, were reduced from 12.5% to 4.1% in those on inorganic nitrates (P = .003).

Looking at longer term outcomes, kidney function was improved at 3 months as measured by change in eGFR, which showed a 10% relative improvement of 5.2 mL/min per 1.73 m² (10%) in the nitrate group vs. the placebo group. Serum creatinine levels were also significantly increased in the nitrate group.

At 12 months, there was a significant 50% relative reduction in major adverse cardiovascular events – including all-cause mortality, recurrent MI, and recurrent revascularization – which were reduced from 18.1% in the placebo group to 9.1% in the nitrate group, with a reduction in all three of the constituent components of the composite endpoint including all-cause mortality.

Major adverse kidney events (all-cause mortality, renal replacement therapy, or persistent renal dysfunction) were also reduced at 12 months from 28.4% in the placebo group to 10.7% in the nitrate group (P < .0001), a 60% relative reduction. This was driven by lower rates of all-cause mortality and persistent renal dysfunction.

While Dr. Jones said these results on major cardiovascular and kidney outcomes should be viewed as hypothesis-generating at the present time, he said there were biological mechanisms that could explain these benefits.

“We saw a reduction in procedural MI, and we know there is a lot of similar biology in preventing procedural MI and subsequent cardiac events in the acute phase. This, in combination with the large reduction in acute kidney injury, could explain why there’s improved outcomes out to 12 months.”

In her comments, Dr. Mehran congratulated the investigators on having conducted the first study to have shown benefit in the prevention of contrast-associated acute kidney injury as well as major adverse cardiovascular and kidney events associated with the condition.

She used the term “contrast-associated acute kidney injury” rather than “contrast-induced nephropathy” because, she said, it has not been proven that the acute kidney injury seen after angiography is actually caused by the contrast and “so many other things are occurring during procedures when these patients are presenting with different syndromes.”

Dr. Mehran pointed out some weaknesses in the NITRATE-CIN study including the single-center design, the large volume of contrast administered, 13% of patients missing the primary endpoint blood draw, and an imbalance in relevant baseline characteristics despite randomization.

The NITRATE-CIN study was funded by Heart Research UK. Dr. Jones has disclosed no relevant financial relationships.

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

AMSTERDAM – A simple, low-cost 5-day course of dietary inorganic nitrate has shown apparent overwhelming benefit in preventing contrast-induced nephropathy (CIN) and reducing subsequent renal and cardiovascular outcomes.

In the NITRATE-CIN Study, non-ST segment elevation myocardial infarction acute coronary syndrome (ACS) patients at risk of renal injury from coronary angiography who received dietary inorganic nitrates had a 70% reduction in CIN compared with those given placebo.

The nitrate group also showed an impressive reduction in periprocedural myocardial infarction (MI) and improved renal function at 3 months, as well as a halving of major adverse cardiovascular events and major adverse kidney events at 1 year.

The trial was presented by Dan Jones, MD, Barts Health NHS Trust, London, at the annual congress of the European Society of Cardiology.

“Currently, aside from intravenous hydration, there is no proven treatment that reduces contrast-induced nephropathy. We feel that dietary inorganic nitrate shows huge promise in this study, and these findings could have important implications in reducing this serious complication of coronary angiography,” Dr. Jones concluded.

He explained that the product used was a formulation of dietary inorganic nitrates given as potassium nitrate capsules, which the study investigators produced specifically for this trial.

At this point, “the only way to get inorganic nitrate is in the diet – specifically by consuming beetroot juice or green leafy vegetables such as spinach and rocket. From a clinician perspective, while these results suggest this is an effective therapy and has great potential, it is not currently possible to prescribe the medication we used in our study, although we are working on producing a commercial product,” he said in an interview.

However, Dr. Jones noted that it is possible to buy beetroot shots, which contain 7 mmol of potassium nitrate in each shot, from health food shops and websites, and two such shots per day for 5 days would give a dose similar to that used in this study, starting the day before angiography.

“While we need a larger multicenter study to confirm these results, studies so far suggest no signal at all that there is any harm in this approach, and there could be a great deal of benefit in taking a couple of beetroot shots prior to and for a few days after an angiogram,” he said.
 

Dietary nitrates “make sense”

Designated discussant of the NITRATE-CIN trial at the ESC Hotline session, Roxanna Mehran, MD, Icahn School of Medicine at Mount Sinai, New York, said the study was well designed, and the “interesting and plausible” hypothesis to raise nitric oxide levels by dietary nitrates “makes sense.”

On the main findings of a major significant 50% reduction in acute kidney injury, Dr. Mehran said, “It is difficult to imagine such a reduction is possible.”

She pointed out that the large reduction in major adverse cardiac events and major adverse kidney events at 1 year also suggests that there is a sustained benefit in protecting the kidney.

“We’re all going to get on beet juice after this,” she quipped.

Still, Dr. Mehran questioned whether the results were “too good to be true,” adding that a larger trial actually powered for longer term outcome events is needed, as well as a better understanding of whether CIN has a causative role in mortality.

Responding to questions about whether such a large effect could actually be achieved with dietary nitrates, Dr. Jones said he thought there would definitely be some benefits, but maybe not quite as large as those seen in this study.

“From our pilot data we thought nitrate may be effective in preventing CIN,” he said in an interview. “We recruited a higher risk group than we thought, which is why the control event rates were higher than we expected, but the acute kidney injury reduction is roughly what we had estimated, and makes sense biologically.”

Dr. Jones acknowledged that the large reductions in long-term major adverse cardiovascular and kidney events were unexpected.

“The trial was not powered to see reductions in these outcomes, so we need to see if those event reductions can be replicated in larger multicenter trials,” he said. “But this was a double-blind placebo-controlled trial so in this trial the effects are real, and I think the effect size in this trial is too large for there not to be a beneficial effect.

“But I’m not so sure that we would see the same magnitude of effect when we have a larger study with tighter confidence intervals but perhaps a 20%-25% reduction in cardiovascular and kidney may be more realistic, which would still be amazing for such an easy and cost-effective intervention,” Dr. Jones added.

A larger trial is now being planned.

The researchers are also working on the development of a commercial form of dietary inorganic nitrate that would be needed for larger multicenter studies and would then be generally available. “We want this to be a low-cost product that would be available to all,” Dr. Jones said.

He noted that other studies have shown that dietary inorganic nitrates in the form of beetroot juice lower blood pressure; there are suggestions it may also lower cholesterol and prevent stent restenosis, and athletes sometimes take it to increase their aerobic capacity.

“There appears to be many benefits of dietary nitrates, and the one thing we can do at this time is to encourage people to increase their dietary nitrate consumption by eating large quantities of green leafy vegetables and beetroot,” Dr. Jones said.
 

Replacing lost nitric oxide

In his presentation, Dr. Jones noted that CIN is a serious complication after coronary angiography and is associated with longer hospital stays, worse long-term kidney function, and increased risk of MI and death.

The incidence varies depending on patient risk and definitions used, but it can affect up to 50% of high-risk ACS patients – older patients and/or those with heart failure, chronic kidney disease, or diabetes.

“We don’t really understand the mechanisms that cause CIN, but multiple proposed mechanisms exist, and we know from previous studies that a deficiency of nitric oxide is crucial to the development of CIN,” he explained. “We also know that [nitric oxide] is crucial for normal renal hemostasis. Therefore, a potential therapeutic target to prevent CIN would be to replace this lost nitric oxide.”

The inorganic nitrate evaluated in this trial is found in the diet, is produced endogenously, and is different from medicinally synthesized organic nitrates such as isosorbide mononitrate, he said.

“Isosorbide mononitrate/dinitrate tablets contain organic nitrates and while they are good for angina, we know that they do not have the same beneficial effects on the sustained generation of nitric oxide as inorganic nitrates,” Dr. Jones added.
 

NITRATE-CIN study

NITRATE-CIN was a double-blind, randomized, placebo-controlled trial conducted at Queen Mary University of London and St. Bartholomew’s Hospital in London, which tested the effectiveness of inorganic nitrate in preventing contrast-induced nephropathy in 640 patients with non-ST elevation ACS referred for invasive coronary angiography.

To be eligible for the trial, patients had to be at risk of contrast-induced nephropathy with an estimated glomerular filtration rate (eGFR) less than 60 mL/min per 1.73 m² or have two of the following significant risk factors: diabetes, liver failure, over 70 years of age, exposure to contrast within 7 days, heart failure, or on concomitant renally acting drugs.

Patients were randomly assigned to a formulation of potassium nitrate (12 mmol/744 mg nitrate) per day given as capsules for a 5-day course with the first dose administered prior to angiography or to a control group that received potassium chloride with a matched potassium concentration.

The patient population had a mean age of 71 years, 73% were male, 75% were White, 46% had diabetes, and 56% had chronic kidney disease. There was a 13% loss to follow-up, which was attributed to the COVID pandemic.

The amount of contrast administration was 180 mL in the placebo and 170 mL in the nitrate arm, with 50% of patients undergoing some sort of revascularization.

The primary endpoint was the incidence of CIN as defined by KDIGO criteria – a series of stages of acute kidney injury defined by changes in serum creatinine within 72 hours and up to 1 week.

Results showed that this primary CIN endpoint was reduced significantly from 30% in the placebo arm to 9.1% in the nitrate group, a 70% relative risk reduction (P < .0001). The majority (90%) of this CIN was stage 1, but 10% was stage 2.

Consistent results were seen when an alternative definition of CIN (Mehran) was used, although the rates in both arms were lower than when the KDIGO definition was used.

The benefit was seen across prespecified subgroups including diabetes status, troponin positivity, and Mehran risk. But the benefit seemed to be attenuated in patients on preexisting organic nitrate therapy, although the numbers in these groups were too small to draw definitive conclusions.

As would be expected, there were significant elevations in both systemic nitrate and nitrite levels both up to 72 hours after the procedure, which was consistent with the 5-day course. This was associated with reductions in systolic and diastolic blood pressure, but not associated with any adverse events, Dr. Jones reported.

Rates of procedural MI, a prespecified secondary endpoint, were reduced from 12.5% to 4.1% in those on inorganic nitrates (P = .003).

Looking at longer term outcomes, kidney function was improved at 3 months as measured by change in eGFR, which showed a 10% relative improvement of 5.2 mL/min per 1.73 m² (10%) in the nitrate group vs. the placebo group. Serum creatinine levels were also significantly increased in the nitrate group.

At 12 months, there was a significant 50% relative reduction in major adverse cardiovascular events – including all-cause mortality, recurrent MI, and recurrent revascularization – which were reduced from 18.1% in the placebo group to 9.1% in the nitrate group, with a reduction in all three of the constituent components of the composite endpoint including all-cause mortality.

Major adverse kidney events (all-cause mortality, renal replacement therapy, or persistent renal dysfunction) were also reduced at 12 months from 28.4% in the placebo group to 10.7% in the nitrate group (P < .0001), a 60% relative reduction. This was driven by lower rates of all-cause mortality and persistent renal dysfunction.

While Dr. Jones said these results on major cardiovascular and kidney outcomes should be viewed as hypothesis-generating at the present time, he said there were biological mechanisms that could explain these benefits.

“We saw a reduction in procedural MI, and we know there is a lot of similar biology in preventing procedural MI and subsequent cardiac events in the acute phase. This, in combination with the large reduction in acute kidney injury, could explain why there’s improved outcomes out to 12 months.”

In her comments, Dr. Mehran congratulated the investigators on having conducted the first study to have shown benefit in the prevention of contrast-associated acute kidney injury as well as major adverse cardiovascular and kidney events associated with the condition.

She used the term “contrast-associated acute kidney injury” rather than “contrast-induced nephropathy” because, she said, it has not been proven that the acute kidney injury seen after angiography is actually caused by the contrast and “so many other things are occurring during procedures when these patients are presenting with different syndromes.”

Dr. Mehran pointed out some weaknesses in the NITRATE-CIN study including the single-center design, the large volume of contrast administered, 13% of patients missing the primary endpoint blood draw, and an imbalance in relevant baseline characteristics despite randomization.

The NITRATE-CIN study was funded by Heart Research UK. Dr. Jones has disclosed no relevant financial relationships.

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

AMSTERDAM – A simple, low-cost 5-day course of dietary inorganic nitrate has shown apparent overwhelming benefit in preventing contrast-induced nephropathy (CIN) and reducing subsequent renal and cardiovascular outcomes.

In the NITRATE-CIN Study, non-ST segment elevation myocardial infarction acute coronary syndrome (ACS) patients at risk of renal injury from coronary angiography who received dietary inorganic nitrates had a 70% reduction in CIN compared with those given placebo.

The nitrate group also showed an impressive reduction in periprocedural myocardial infarction (MI) and improved renal function at 3 months, as well as a halving of major adverse cardiovascular events and major adverse kidney events at 1 year.

The trial was presented by Dan Jones, MD, Barts Health NHS Trust, London, at the annual congress of the European Society of Cardiology.

“Currently, aside from intravenous hydration, there is no proven treatment that reduces contrast-induced nephropathy. We feel that dietary inorganic nitrate shows huge promise in this study, and these findings could have important implications in reducing this serious complication of coronary angiography,” Dr. Jones concluded.

He explained that the product used was a formulation of dietary inorganic nitrates given as potassium nitrate capsules, which the study investigators produced specifically for this trial.

At this point, “the only way to get inorganic nitrate is in the diet – specifically by consuming beetroot juice or green leafy vegetables such as spinach and rocket. From a clinician perspective, while these results suggest this is an effective therapy and has great potential, it is not currently possible to prescribe the medication we used in our study, although we are working on producing a commercial product,” he said in an interview.

However, Dr. Jones noted that it is possible to buy beetroot shots, which contain 7 mmol of potassium nitrate in each shot, from health food shops and websites, and two such shots per day for 5 days would give a dose similar to that used in this study, starting the day before angiography.

“While we need a larger multicenter study to confirm these results, studies so far suggest no signal at all that there is any harm in this approach, and there could be a great deal of benefit in taking a couple of beetroot shots prior to and for a few days after an angiogram,” he said.
 

Dietary nitrates “make sense”

Designated discussant of the NITRATE-CIN trial at the ESC Hotline session, Roxanna Mehran, MD, Icahn School of Medicine at Mount Sinai, New York, said the study was well designed, and the “interesting and plausible” hypothesis to raise nitric oxide levels by dietary nitrates “makes sense.”

On the main findings of a major significant 50% reduction in acute kidney injury, Dr. Mehran said, “It is difficult to imagine such a reduction is possible.”

She pointed out that the large reduction in major adverse cardiac events and major adverse kidney events at 1 year also suggests that there is a sustained benefit in protecting the kidney.

“We’re all going to get on beet juice after this,” she quipped.

Still, Dr. Mehran questioned whether the results were “too good to be true,” adding that a larger trial actually powered for longer term outcome events is needed, as well as a better understanding of whether CIN has a causative role in mortality.

Responding to questions about whether such a large effect could actually be achieved with dietary nitrates, Dr. Jones said he thought there would definitely be some benefits, but maybe not quite as large as those seen in this study.

“From our pilot data we thought nitrate may be effective in preventing CIN,” he said in an interview. “We recruited a higher risk group than we thought, which is why the control event rates were higher than we expected, but the acute kidney injury reduction is roughly what we had estimated, and makes sense biologically.”

Dr. Jones acknowledged that the large reductions in long-term major adverse cardiovascular and kidney events were unexpected.

“The trial was not powered to see reductions in these outcomes, so we need to see if those event reductions can be replicated in larger multicenter trials,” he said. “But this was a double-blind placebo-controlled trial so in this trial the effects are real, and I think the effect size in this trial is too large for there not to be a beneficial effect.

“But I’m not so sure that we would see the same magnitude of effect when we have a larger study with tighter confidence intervals but perhaps a 20%-25% reduction in cardiovascular and kidney may be more realistic, which would still be amazing for such an easy and cost-effective intervention,” Dr. Jones added.

A larger trial is now being planned.

The researchers are also working on the development of a commercial form of dietary inorganic nitrate that would be needed for larger multicenter studies and would then be generally available. “We want this to be a low-cost product that would be available to all,” Dr. Jones said.

He noted that other studies have shown that dietary inorganic nitrates in the form of beetroot juice lower blood pressure; there are suggestions it may also lower cholesterol and prevent stent restenosis, and athletes sometimes take it to increase their aerobic capacity.

“There appears to be many benefits of dietary nitrates, and the one thing we can do at this time is to encourage people to increase their dietary nitrate consumption by eating large quantities of green leafy vegetables and beetroot,” Dr. Jones said.
 

Replacing lost nitric oxide

In his presentation, Dr. Jones noted that CIN is a serious complication after coronary angiography and is associated with longer hospital stays, worse long-term kidney function, and increased risk of MI and death.

The incidence varies depending on patient risk and definitions used, but it can affect up to 50% of high-risk ACS patients – older patients and/or those with heart failure, chronic kidney disease, or diabetes.

“We don’t really understand the mechanisms that cause CIN, but multiple proposed mechanisms exist, and we know from previous studies that a deficiency of nitric oxide is crucial to the development of CIN,” he explained. “We also know that [nitric oxide] is crucial for normal renal hemostasis. Therefore, a potential therapeutic target to prevent CIN would be to replace this lost nitric oxide.”

The inorganic nitrate evaluated in this trial is found in the diet, is produced endogenously, and is different from medicinally synthesized organic nitrates such as isosorbide mononitrate, he said.

“Isosorbide mononitrate/dinitrate tablets contain organic nitrates and while they are good for angina, we know that they do not have the same beneficial effects on the sustained generation of nitric oxide as inorganic nitrates,” Dr. Jones added.
 

NITRATE-CIN study

NITRATE-CIN was a double-blind, randomized, placebo-controlled trial conducted at Queen Mary University of London and St. Bartholomew’s Hospital in London, which tested the effectiveness of inorganic nitrate in preventing contrast-induced nephropathy in 640 patients with non-ST elevation ACS referred for invasive coronary angiography.

To be eligible for the trial, patients had to be at risk of contrast-induced nephropathy with an estimated glomerular filtration rate (eGFR) less than 60 mL/min per 1.73 m² or have two of the following significant risk factors: diabetes, liver failure, over 70 years of age, exposure to contrast within 7 days, heart failure, or on concomitant renally acting drugs.

Patients were randomly assigned to a formulation of potassium nitrate (12 mmol/744 mg nitrate) per day given as capsules for a 5-day course with the first dose administered prior to angiography or to a control group that received potassium chloride with a matched potassium concentration.

The patient population had a mean age of 71 years, 73% were male, 75% were White, 46% had diabetes, and 56% had chronic kidney disease. There was a 13% loss to follow-up, which was attributed to the COVID pandemic.

The amount of contrast administration was 180 mL in the placebo and 170 mL in the nitrate arm, with 50% of patients undergoing some sort of revascularization.

The primary endpoint was the incidence of CIN as defined by KDIGO criteria – a series of stages of acute kidney injury defined by changes in serum creatinine within 72 hours and up to 1 week.

Results showed that this primary CIN endpoint was reduced significantly from 30% in the placebo arm to 9.1% in the nitrate group, a 70% relative risk reduction (P < .0001). The majority (90%) of this CIN was stage 1, but 10% was stage 2.

Consistent results were seen when an alternative definition of CIN (Mehran) was used, although the rates in both arms were lower than when the KDIGO definition was used.

The benefit was seen across prespecified subgroups including diabetes status, troponin positivity, and Mehran risk. But the benefit seemed to be attenuated in patients on preexisting organic nitrate therapy, although the numbers in these groups were too small to draw definitive conclusions.

As would be expected, there were significant elevations in both systemic nitrate and nitrite levels both up to 72 hours after the procedure, which was consistent with the 5-day course. This was associated with reductions in systolic and diastolic blood pressure, but not associated with any adverse events, Dr. Jones reported.

Rates of procedural MI, a prespecified secondary endpoint, were reduced from 12.5% to 4.1% in those on inorganic nitrates (P = .003).

Looking at longer term outcomes, kidney function was improved at 3 months as measured by change in eGFR, which showed a 10% relative improvement of 5.2 mL/min per 1.73 m² (10%) in the nitrate group vs. the placebo group. Serum creatinine levels were also significantly increased in the nitrate group.

At 12 months, there was a significant 50% relative reduction in major adverse cardiovascular events – including all-cause mortality, recurrent MI, and recurrent revascularization – which were reduced from 18.1% in the placebo group to 9.1% in the nitrate group, with a reduction in all three of the constituent components of the composite endpoint including all-cause mortality.

Major adverse kidney events (all-cause mortality, renal replacement therapy, or persistent renal dysfunction) were also reduced at 12 months from 28.4% in the placebo group to 10.7% in the nitrate group (P < .0001), a 60% relative reduction. This was driven by lower rates of all-cause mortality and persistent renal dysfunction.

While Dr. Jones said these results on major cardiovascular and kidney outcomes should be viewed as hypothesis-generating at the present time, he said there were biological mechanisms that could explain these benefits.

“We saw a reduction in procedural MI, and we know there is a lot of similar biology in preventing procedural MI and subsequent cardiac events in the acute phase. This, in combination with the large reduction in acute kidney injury, could explain why there’s improved outcomes out to 12 months.”

In her comments, Dr. Mehran congratulated the investigators on having conducted the first study to have shown benefit in the prevention of contrast-associated acute kidney injury as well as major adverse cardiovascular and kidney events associated with the condition.

She used the term “contrast-associated acute kidney injury” rather than “contrast-induced nephropathy” because, she said, it has not been proven that the acute kidney injury seen after angiography is actually caused by the contrast and “so many other things are occurring during procedures when these patients are presenting with different syndromes.”

Dr. Mehran pointed out some weaknesses in the NITRATE-CIN study including the single-center design, the large volume of contrast administered, 13% of patients missing the primary endpoint blood draw, and an imbalance in relevant baseline characteristics despite randomization.

The NITRATE-CIN study was funded by Heart Research UK. Dr. Jones has disclosed no relevant financial relationships.

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