Mitchel L. Zoler, PhD

PARIS – Patients with angina who were also more than 3 months out from a prior MI had a significantly increased rate of subsequent cardiovascular death or nonfatal MI in a study of nearly 33,000 patients, a finding that identified angina as a new red flag when following post-MI patients.

Mitchel L. Zoler/MDedge News

“Angina and prior MI was a higher-risk subgroup that may warrant more intensive management. This is new,” Emmanuel Sorbets, MD, said at the annual congress of the European Society of Cardiology.

The finding came from review of 32,703 patients from 45 countries with stable coronary artery disease enrolled in the CLARIFY (Prospective Observational Longitudinal Registry of Patients with Stable Coronary Artery Disease) registry during 2009-2010, a population that appeared to uniformly meet the new definition of chronic chromic syndromes recently published by a task force of the society (Eur Heart J. 2019 Aug 31. doi: 10.1093/eurheartj/ehz425).

Among the CLARIFY patients, 60% had an MI more than 3 months prior to enrollment (the registry excluded patients with more proximate MIs), and in this subgroup angina at baseline was linked with a 3.6% absolute increase in the rate of cardiovascular death or nonfatal MI compared with post-MI patients without angina at baseline during a median 5 year follow-up. This translated into a 44% relative increase that remained statistically significant after adjustment for several demographic and clinical factors, said Dr. Sorbets, a cardiologist at Avicenne Hospital in Bobigny, France. The cumulative incidence of the combined endpoint was 11.8% among post-MI patients with baseline angina and 8.2% in those without angina. Among patients without a prior MI, the presence or absence of angina at entry into the registry had no link with the incidence of later outcomes. Concurrently with Dr. Sorbets’ report at the congress, the results appeared in an article published online (Eur Heart J. 2019 Sep 3;doi: 10.1093/eurheartj/ehz660).

This finding should immediately influence practice, said Sanjay Sharma, MD, professor of inherited cardiac diseases and sports cardiology at St. George’s University, London. “One of the messages from this study is that we now have a very easy way to measure a high-risk factor,” and that patients who present with angina more than 3 months after an MI “require intensive investigation and aggressive management,” he said. The new evidence identified post-MI patients with angina as having a “semi-urgent” condition that needs added anti-anginal treatment and, if symptoms persist, possible revascularization, especially patients without prior revascularization, he said in a video interview. Although the study did not analyze the type of MI linked with these poor outcomes, Dr. Sharma speculated that certain patients with a prior non ST-elevation MI may face the greatest danger it they did not undergo percutaneous coronary revascularization at the time of their MI.

CLARIFY is sponsored by Servier. Dr. Sorbets has received personal fees from Servier, AstraZeneca, Bayer, Bristol-Myers Squibb, Merck Sharpe & Dohme, and Novartis. Dr. Sharma had no relevant disclosures.

[email protected]

PARIS – Patients with angina who were also more than 3 months out from a prior MI had a significantly increased rate of subsequent cardiovascular death or nonfatal MI in a study of nearly 33,000 patients, a finding that identified angina as a new red flag when following post-MI patients.

Mitchel L. Zoler/MDedge News

“Angina and prior MI was a higher-risk subgroup that may warrant more intensive management. This is new,” Emmanuel Sorbets, MD, said at the annual congress of the European Society of Cardiology.

The finding came from review of 32,703 patients from 45 countries with stable coronary artery disease enrolled in the CLARIFY (Prospective Observational Longitudinal Registry of Patients with Stable Coronary Artery Disease) registry during 2009-2010, a population that appeared to uniformly meet the new definition of chronic chromic syndromes recently published by a task force of the society (Eur Heart J. 2019 Aug 31. doi: 10.1093/eurheartj/ehz425).

Among the CLARIFY patients, 60% had an MI more than 3 months prior to enrollment (the registry excluded patients with more proximate MIs), and in this subgroup angina at baseline was linked with a 3.6% absolute increase in the rate of cardiovascular death or nonfatal MI compared with post-MI patients without angina at baseline during a median 5 year follow-up. This translated into a 44% relative increase that remained statistically significant after adjustment for several demographic and clinical factors, said Dr. Sorbets, a cardiologist at Avicenne Hospital in Bobigny, France. The cumulative incidence of the combined endpoint was 11.8% among post-MI patients with baseline angina and 8.2% in those without angina. Among patients without a prior MI, the presence or absence of angina at entry into the registry had no link with the incidence of later outcomes. Concurrently with Dr. Sorbets’ report at the congress, the results appeared in an article published online (Eur Heart J. 2019 Sep 3;doi: 10.1093/eurheartj/ehz660).

This finding should immediately influence practice, said Sanjay Sharma, MD, professor of inherited cardiac diseases and sports cardiology at St. George’s University, London. “One of the messages from this study is that we now have a very easy way to measure a high-risk factor,” and that patients who present with angina more than 3 months after an MI “require intensive investigation and aggressive management,” he said. The new evidence identified post-MI patients with angina as having a “semi-urgent” condition that needs added anti-anginal treatment and, if symptoms persist, possible revascularization, especially patients without prior revascularization, he said in a video interview. Although the study did not analyze the type of MI linked with these poor outcomes, Dr. Sharma speculated that certain patients with a prior non ST-elevation MI may face the greatest danger it they did not undergo percutaneous coronary revascularization at the time of their MI.

CLARIFY is sponsored by Servier. Dr. Sorbets has received personal fees from Servier, AstraZeneca, Bayer, Bristol-Myers Squibb, Merck Sharpe & Dohme, and Novartis. Dr. Sharma had no relevant disclosures.

[email protected]

PARIS – Patients with angina who were also more than 3 months out from a prior MI had a significantly increased rate of subsequent cardiovascular death or nonfatal MI in a study of nearly 33,000 patients, a finding that identified angina as a new red flag when following post-MI patients.

Mitchel L. Zoler/MDedge News

“Angina and prior MI was a higher-risk subgroup that may warrant more intensive management. This is new,” Emmanuel Sorbets, MD, said at the annual congress of the European Society of Cardiology.

The finding came from review of 32,703 patients from 45 countries with stable coronary artery disease enrolled in the CLARIFY (Prospective Observational Longitudinal Registry of Patients with Stable Coronary Artery Disease) registry during 2009-2010, a population that appeared to uniformly meet the new definition of chronic chromic syndromes recently published by a task force of the society (Eur Heart J. 2019 Aug 31. doi: 10.1093/eurheartj/ehz425).

Among the CLARIFY patients, 60% had an MI more than 3 months prior to enrollment (the registry excluded patients with more proximate MIs), and in this subgroup angina at baseline was linked with a 3.6% absolute increase in the rate of cardiovascular death or nonfatal MI compared with post-MI patients without angina at baseline during a median 5 year follow-up. This translated into a 44% relative increase that remained statistically significant after adjustment for several demographic and clinical factors, said Dr. Sorbets, a cardiologist at Avicenne Hospital in Bobigny, France. The cumulative incidence of the combined endpoint was 11.8% among post-MI patients with baseline angina and 8.2% in those without angina. Among patients without a prior MI, the presence or absence of angina at entry into the registry had no link with the incidence of later outcomes. Concurrently with Dr. Sorbets’ report at the congress, the results appeared in an article published online (Eur Heart J. 2019 Sep 3;doi: 10.1093/eurheartj/ehz660).

This finding should immediately influence practice, said Sanjay Sharma, MD, professor of inherited cardiac diseases and sports cardiology at St. George’s University, London. “One of the messages from this study is that we now have a very easy way to measure a high-risk factor,” and that patients who present with angina more than 3 months after an MI “require intensive investigation and aggressive management,” he said. The new evidence identified post-MI patients with angina as having a “semi-urgent” condition that needs added anti-anginal treatment and, if symptoms persist, possible revascularization, especially patients without prior revascularization, he said in a video interview. Although the study did not analyze the type of MI linked with these poor outcomes, Dr. Sharma speculated that certain patients with a prior non ST-elevation MI may face the greatest danger it they did not undergo percutaneous coronary revascularization at the time of their MI.

CLARIFY is sponsored by Servier. Dr. Sorbets has received personal fees from Servier, AstraZeneca, Bayer, Bristol-Myers Squibb, Merck Sharpe & Dohme, and Novartis. Dr. Sharma had no relevant disclosures.

[email protected]

PARIS – The 2019 dyslipidemia management guidelines from the European Society of Cardiology set an LDL cholesterol target for very-high-risk people of less than 55 mg/dL (as well as at least a 50% cut from baseline), a class I recommendation. This marks the first time a cardiology society has either recommended a target goal for this measure below 70 mg/dL or endorsed treating patients to still-lower cholesterol once their level was already under 70 mg/dL.*

The guidelines went further by suggesting consideration of an even lower treatment target for LDL-cholesterol in very-high-risk, secondary prevention patients who have already had at least two atherosclerotic cardiovascular disease events during the past 2 years, a setting that could justify an LDL-cholesterol goal of less than 40 mg/dL (along with a cut from baseline of at least 50%), a class IIb recommendation that denotes a “may be considered,” endorsement.

“In all the trials, lower was better. There was no lower level of LDL cholesterol that’s been studied that was not better” for patient outcomes, Colin Baigent, BMBCH, said while presenting the new guideline at the annual congress of the European Society of Cardiology (ESC). “It’s very clear” that the full treatment benefit from lowering LDL-cholesterol extends to getting very-high risk patients below these levels, said Dr. Baigent, professor of cardiology at Oxford (England) University and one of three chairs of the ESC’s dyslipidemia guideline-writing panel.

While this change was seen as a notably aggressive goal and too fixed on a specific number by at least one author of the 2018 American Heart Association/American College of Cardiology cholesterol management guideline (J Am Coll Cardiol. 2019 Jun;73[24]:e285-e350), it was embraced by another U.S. expert not involved in writing the most recent U.S. recommendations.

“A goal for LDL-cholesterol of less than 55 mg/dL is reasonable; it’s well documented” by trial evidence “and I support it,” said Robert H. Eckel, MD, an endocrinologist and professor of medicine at the University of Colorado in Aurora. Dr. Eckel added that he “also supports” an LDL-cholesterol of less than 40 mg/dL in very-high-risk patients with a history of multiple events or with multiple residual risk factors, and he said he has applied this lower LDL-cholesterol goal in his practice for selected patients. But Dr. Eckel acknowledged in an interview that the evidence for it was less clear-cut than was the evidence behind a goal of less than 55 mg/dL. He also supported the concept of including a treatment goal in U.S. lipid recommendations, which in recent versions has been missing. “I fall back on a cholesterol goal for practical purposes” of making the success of cholesterol-lowering treatment easier to track.

The new ESC goal was characterized as “arbitrary” by Neil J. Stone, MD, vice-chair of the panel that wrote the 2018 AHA/ACC guideline, which relied on treating secondary-prevention patients at high risk to an LDL-cholesterol at least 50% less than before treatment, and recommended continued intensification for patients whose LDL-cholesterol level remained at or above 70 mg/dL.

“If the patient is at 58 mg/dL I’m not sure anyone can tell me what the difference is,” compared with reaching less than 55 mg/dL, Dr. Stone said in an interview. “I worry about focusing on a number and not on the concept that people at the very highest risk deserve the most intensive treatment; the Europeans agree, but they have a different way of looking at it. Despite this difference in approach, the new ESC guidelines and the 2018 U.S. guideline “are more similar than different,” stressed Dr. Stone, professor of medicine and preventive medicine at Northwestern University, Chicago.

“It’s a mind shift that clinicians need to be most aggressive in treating patients with the highest risk” even when their LDL-cholesterol is low but not yet at the target level, Dr. Collins said during a discussion session at the congress.

The new ESC guidelines is about “both getting the LDL-cholesterol down to a certain level and also about achieving a big [at least 50%] change” from baseline. “I think the ESC guidelines make that crystal clear,” said Marc S. Sabatine, MD, professor of medicine at Harvard Medical School, Boston, and the sole American to participate in the ESC guidelines-writing panel.

Mitchel L. Zoler/MDedge News

“I commend the [ESC] guideline for focusing on the science and on what is best for patients. The U.S. guidelines conflated the science and the cost, and the recommendations got watered down by cost considerations,” said Dr. Sabatine, who has led several studies of PCSK9 inhibitors.

Dr. Baigent added that the panel “deliberated long and hard on cost, but we felt that we had to focus on the evidence. The cost will shift” in the future, he predicted.

Other U.S. physicians highlighted the need to take drug cost into account when writing public health policy documents such as lipid-management guidelines and questioned whether this more liberal use of PCSK9 inhibitors was justified.

“I think that in the absence of familial hypercholesterolemia you need to waffle around the edges to justify a PCSK9 inhibitor,” said Dr. Eckel. “The cost of PCSK9 inhibitors has come down, but at $6,000 per year you can’t ignore their cost.”

“In the U.S. we need to be mindful of the cost of treatment,” said Dr. Stone. “The ESC guidelines are probably more aggressive” than the 2018 U.S. guideline. “They use PCSK9 inhibitors perhaps more than we do; we [in the United States] prefer generic ezetimibe. A lot has to do with the definitions of risk. The European guidelines have a lot of risk definitions that differ” from the U.S. guideline, he said.

Members of the ESC guidelines panel acknowledged that the SCORE risk-assessment charts could overestimate risk in older people who need primary prevention treatment, as well as underestimate the risk in younger adults.

This inherent age bias in the SCORE risk tables make it “extremely important to contextualize” a person’s risk “by considering other risk factors,” advised Brian A. Ference, MD, an interventional cardiologist and professor at Cambridge (England) University who was a member of the ESC guidelines writing group.

The new ESC guidelines say that risk categorization “must be interpreted in light of the clinician’s knowledge and experience, and of the patient’s pretest likelihood” of cardiovascular disease.”

Dr. Baigent has received research funding from Boehringer Ingelheim, Novartis, and Pfizer. Dr. Eckel has been an expert witness on behalf of Sanofi/Regeneron. Dr. Sabatine and Dr. Ference have received honoraria and research funding from several companies including those that market lipid-lowering drugs. Dr. Stone and Dr. Collins had no disclosures.

*Correction, 9/20/19: A previous version of this article incorrectly stated that the ESC guidelines were the first by a medical society to recommend the lower cholesterol goals. The American Association of Clinical Endocrinologists included targets below 55 mg/dL in their 2017 dyslipidemia management guidelines.

[email protected]

SOURCE: Mach F et al. Eur Heart J. 2019 Aug 31. doi: 10.1093/eurheartj/ehz455.

PARIS – The 2019 dyslipidemia management guidelines from the European Society of Cardiology set an LDL cholesterol target for very-high-risk people of less than 55 mg/dL (as well as at least a 50% cut from baseline), a class I recommendation. This marks the first time a cardiology society has either recommended a target goal for this measure below 70 mg/dL or endorsed treating patients to still-lower cholesterol once their level was already under 70 mg/dL.*

The guidelines went further by suggesting consideration of an even lower treatment target for LDL-cholesterol in very-high-risk, secondary prevention patients who have already had at least two atherosclerotic cardiovascular disease events during the past 2 years, a setting that could justify an LDL-cholesterol goal of less than 40 mg/dL (along with a cut from baseline of at least 50%), a class IIb recommendation that denotes a “may be considered,” endorsement.

“In all the trials, lower was better. There was no lower level of LDL cholesterol that’s been studied that was not better” for patient outcomes, Colin Baigent, BMBCH, said while presenting the new guideline at the annual congress of the European Society of Cardiology (ESC). “It’s very clear” that the full treatment benefit from lowering LDL-cholesterol extends to getting very-high risk patients below these levels, said Dr. Baigent, professor of cardiology at Oxford (England) University and one of three chairs of the ESC’s dyslipidemia guideline-writing panel.

While this change was seen as a notably aggressive goal and too fixed on a specific number by at least one author of the 2018 American Heart Association/American College of Cardiology cholesterol management guideline (J Am Coll Cardiol. 2019 Jun;73[24]:e285-e350), it was embraced by another U.S. expert not involved in writing the most recent U.S. recommendations.

“A goal for LDL-cholesterol of less than 55 mg/dL is reasonable; it’s well documented” by trial evidence “and I support it,” said Robert H. Eckel, MD, an endocrinologist and professor of medicine at the University of Colorado in Aurora. Dr. Eckel added that he “also supports” an LDL-cholesterol of less than 40 mg/dL in very-high-risk patients with a history of multiple events or with multiple residual risk factors, and he said he has applied this lower LDL-cholesterol goal in his practice for selected patients. But Dr. Eckel acknowledged in an interview that the evidence for it was less clear-cut than was the evidence behind a goal of less than 55 mg/dL. He also supported the concept of including a treatment goal in U.S. lipid recommendations, which in recent versions has been missing. “I fall back on a cholesterol goal for practical purposes” of making the success of cholesterol-lowering treatment easier to track.

The new ESC goal was characterized as “arbitrary” by Neil J. Stone, MD, vice-chair of the panel that wrote the 2018 AHA/ACC guideline, which relied on treating secondary-prevention patients at high risk to an LDL-cholesterol at least 50% less than before treatment, and recommended continued intensification for patients whose LDL-cholesterol level remained at or above 70 mg/dL.

“If the patient is at 58 mg/dL I’m not sure anyone can tell me what the difference is,” compared with reaching less than 55 mg/dL, Dr. Stone said in an interview. “I worry about focusing on a number and not on the concept that people at the very highest risk deserve the most intensive treatment; the Europeans agree, but they have a different way of looking at it. Despite this difference in approach, the new ESC guidelines and the 2018 U.S. guideline “are more similar than different,” stressed Dr. Stone, professor of medicine and preventive medicine at Northwestern University, Chicago.

“It’s a mind shift that clinicians need to be most aggressive in treating patients with the highest risk” even when their LDL-cholesterol is low but not yet at the target level, Dr. Collins said during a discussion session at the congress.

The new ESC guidelines is about “both getting the LDL-cholesterol down to a certain level and also about achieving a big [at least 50%] change” from baseline. “I think the ESC guidelines make that crystal clear,” said Marc S. Sabatine, MD, professor of medicine at Harvard Medical School, Boston, and the sole American to participate in the ESC guidelines-writing panel.

Mitchel L. Zoler/MDedge News

“I commend the [ESC] guideline for focusing on the science and on what is best for patients. The U.S. guidelines conflated the science and the cost, and the recommendations got watered down by cost considerations,” said Dr. Sabatine, who has led several studies of PCSK9 inhibitors.

Dr. Baigent added that the panel “deliberated long and hard on cost, but we felt that we had to focus on the evidence. The cost will shift” in the future, he predicted.

Other U.S. physicians highlighted the need to take drug cost into account when writing public health policy documents such as lipid-management guidelines and questioned whether this more liberal use of PCSK9 inhibitors was justified.

“I think that in the absence of familial hypercholesterolemia you need to waffle around the edges to justify a PCSK9 inhibitor,” said Dr. Eckel. “The cost of PCSK9 inhibitors has come down, but at $6,000 per year you can’t ignore their cost.”

“In the U.S. we need to be mindful of the cost of treatment,” said Dr. Stone. “The ESC guidelines are probably more aggressive” than the 2018 U.S. guideline. “They use PCSK9 inhibitors perhaps more than we do; we [in the United States] prefer generic ezetimibe. A lot has to do with the definitions of risk. The European guidelines have a lot of risk definitions that differ” from the U.S. guideline, he said.

Members of the ESC guidelines panel acknowledged that the SCORE risk-assessment charts could overestimate risk in older people who need primary prevention treatment, as well as underestimate the risk in younger adults.

This inherent age bias in the SCORE risk tables make it “extremely important to contextualize” a person’s risk “by considering other risk factors,” advised Brian A. Ference, MD, an interventional cardiologist and professor at Cambridge (England) University who was a member of the ESC guidelines writing group.

The new ESC guidelines say that risk categorization “must be interpreted in light of the clinician’s knowledge and experience, and of the patient’s pretest likelihood” of cardiovascular disease.”

Dr. Baigent has received research funding from Boehringer Ingelheim, Novartis, and Pfizer. Dr. Eckel has been an expert witness on behalf of Sanofi/Regeneron. Dr. Sabatine and Dr. Ference have received honoraria and research funding from several companies including those that market lipid-lowering drugs. Dr. Stone and Dr. Collins had no disclosures.

*Correction, 9/20/19: A previous version of this article incorrectly stated that the ESC guidelines were the first by a medical society to recommend the lower cholesterol goals. The American Association of Clinical Endocrinologists included targets below 55 mg/dL in their 2017 dyslipidemia management guidelines.

[email protected]

SOURCE: Mach F et al. Eur Heart J. 2019 Aug 31. doi: 10.1093/eurheartj/ehz455.

PARIS – The 2019 dyslipidemia management guidelines from the European Society of Cardiology set an LDL cholesterol target for very-high-risk people of less than 55 mg/dL (as well as at least a 50% cut from baseline), a class I recommendation. This marks the first time a cardiology society has either recommended a target goal for this measure below 70 mg/dL or endorsed treating patients to still-lower cholesterol once their level was already under 70 mg/dL.*

The guidelines went further by suggesting consideration of an even lower treatment target for LDL-cholesterol in very-high-risk, secondary prevention patients who have already had at least two atherosclerotic cardiovascular disease events during the past 2 years, a setting that could justify an LDL-cholesterol goal of less than 40 mg/dL (along with a cut from baseline of at least 50%), a class IIb recommendation that denotes a “may be considered,” endorsement.

“In all the trials, lower was better. There was no lower level of LDL cholesterol that’s been studied that was not better” for patient outcomes, Colin Baigent, BMBCH, said while presenting the new guideline at the annual congress of the European Society of Cardiology (ESC). “It’s very clear” that the full treatment benefit from lowering LDL-cholesterol extends to getting very-high risk patients below these levels, said Dr. Baigent, professor of cardiology at Oxford (England) University and one of three chairs of the ESC’s dyslipidemia guideline-writing panel.

While this change was seen as a notably aggressive goal and too fixed on a specific number by at least one author of the 2018 American Heart Association/American College of Cardiology cholesterol management guideline (J Am Coll Cardiol. 2019 Jun;73[24]:e285-e350), it was embraced by another U.S. expert not involved in writing the most recent U.S. recommendations.

“A goal for LDL-cholesterol of less than 55 mg/dL is reasonable; it’s well documented” by trial evidence “and I support it,” said Robert H. Eckel, MD, an endocrinologist and professor of medicine at the University of Colorado in Aurora. Dr. Eckel added that he “also supports” an LDL-cholesterol of less than 40 mg/dL in very-high-risk patients with a history of multiple events or with multiple residual risk factors, and he said he has applied this lower LDL-cholesterol goal in his practice for selected patients. But Dr. Eckel acknowledged in an interview that the evidence for it was less clear-cut than was the evidence behind a goal of less than 55 mg/dL. He also supported the concept of including a treatment goal in U.S. lipid recommendations, which in recent versions has been missing. “I fall back on a cholesterol goal for practical purposes” of making the success of cholesterol-lowering treatment easier to track.

The new ESC goal was characterized as “arbitrary” by Neil J. Stone, MD, vice-chair of the panel that wrote the 2018 AHA/ACC guideline, which relied on treating secondary-prevention patients at high risk to an LDL-cholesterol at least 50% less than before treatment, and recommended continued intensification for patients whose LDL-cholesterol level remained at or above 70 mg/dL.

“If the patient is at 58 mg/dL I’m not sure anyone can tell me what the difference is,” compared with reaching less than 55 mg/dL, Dr. Stone said in an interview. “I worry about focusing on a number and not on the concept that people at the very highest risk deserve the most intensive treatment; the Europeans agree, but they have a different way of looking at it. Despite this difference in approach, the new ESC guidelines and the 2018 U.S. guideline “are more similar than different,” stressed Dr. Stone, professor of medicine and preventive medicine at Northwestern University, Chicago.

“It’s a mind shift that clinicians need to be most aggressive in treating patients with the highest risk” even when their LDL-cholesterol is low but not yet at the target level, Dr. Collins said during a discussion session at the congress.

The new ESC guidelines is about “both getting the LDL-cholesterol down to a certain level and also about achieving a big [at least 50%] change” from baseline. “I think the ESC guidelines make that crystal clear,” said Marc S. Sabatine, MD, professor of medicine at Harvard Medical School, Boston, and the sole American to participate in the ESC guidelines-writing panel.

Mitchel L. Zoler/MDedge News

“I commend the [ESC] guideline for focusing on the science and on what is best for patients. The U.S. guidelines conflated the science and the cost, and the recommendations got watered down by cost considerations,” said Dr. Sabatine, who has led several studies of PCSK9 inhibitors.

Dr. Baigent added that the panel “deliberated long and hard on cost, but we felt that we had to focus on the evidence. The cost will shift” in the future, he predicted.

Other U.S. physicians highlighted the need to take drug cost into account when writing public health policy documents such as lipid-management guidelines and questioned whether this more liberal use of PCSK9 inhibitors was justified.

“I think that in the absence of familial hypercholesterolemia you need to waffle around the edges to justify a PCSK9 inhibitor,” said Dr. Eckel. “The cost of PCSK9 inhibitors has come down, but at $6,000 per year you can’t ignore their cost.”

“In the U.S. we need to be mindful of the cost of treatment,” said Dr. Stone. “The ESC guidelines are probably more aggressive” than the 2018 U.S. guideline. “They use PCSK9 inhibitors perhaps more than we do; we [in the United States] prefer generic ezetimibe. A lot has to do with the definitions of risk. The European guidelines have a lot of risk definitions that differ” from the U.S. guideline, he said.

Members of the ESC guidelines panel acknowledged that the SCORE risk-assessment charts could overestimate risk in older people who need primary prevention treatment, as well as underestimate the risk in younger adults.

This inherent age bias in the SCORE risk tables make it “extremely important to contextualize” a person’s risk “by considering other risk factors,” advised Brian A. Ference, MD, an interventional cardiologist and professor at Cambridge (England) University who was a member of the ESC guidelines writing group.

The new ESC guidelines say that risk categorization “must be interpreted in light of the clinician’s knowledge and experience, and of the patient’s pretest likelihood” of cardiovascular disease.”

Dr. Baigent has received research funding from Boehringer Ingelheim, Novartis, and Pfizer. Dr. Eckel has been an expert witness on behalf of Sanofi/Regeneron. Dr. Sabatine and Dr. Ference have received honoraria and research funding from several companies including those that market lipid-lowering drugs. Dr. Stone and Dr. Collins had no disclosures.

*Correction, 9/20/19: A previous version of this article incorrectly stated that the ESC guidelines were the first by a medical society to recommend the lower cholesterol goals. The American Association of Clinical Endocrinologists included targets below 55 mg/dL in their 2017 dyslipidemia management guidelines.

[email protected]

SOURCE: Mach F et al. Eur Heart J. 2019 Aug 31. doi: 10.1093/eurheartj/ehz455.

PARIS – Middle-aged adults with a body mass index of 25-29 kg/m² had a significantly better adjusted survival during a median follow-up of nearly 10 years than did people with a “normal” body mass index of 20-24 kg/m² in a worldwide study of more than 140,000. This finding suggests the current, widely accepted definition of normal body mass index is wrong.*

Mitchel L. Zoler/MDedge News

The new findings suggest that the current definition of a “healthy” body mass index (BMI) “should be re-evaluated,” Darryl P. Leong, MBBS, said at the annual Congress of the European Society of Cardiology. The analysis also identified a BMI specifically of 27 kg/m² as associated with optimal survival among both women and men, “clearly outside the range of 20 to less than 25 kg/m² that is considered normal,” said Dr. Leong, a cardiologist at McMaster University and the Population Health Research Institute, both in Hamilton, Ont.

Dr. Leong cited three potential explanations for why the new study identified optimal survival with a BMI of 25 to less than 30 kg/m² among people who were 35-70 years old when they entered the study and were followed for a median of 9.5 years: The current study collected data and adjusted the results using a wider range of potential confounders than in prior studies, the data reflect the impact of contemporary interventions to reduce cardiovascular disease illness and death while past studies relied on data from earlier times when less cardiovascular disease protection occurred, and the current study included people from lower-income countries, although the finding is just as applicable to people who live in high-income countries, who were also included in the study population, noted Salim Yusuf, MBBS, principal investigator for the study.

A BMI of 20-24 kg/m² “is actually low and harmful,” noted Dr. Yusuf in an interview. Despite recent data consistently showing better survival among people with a BMI of 25-29 kg/m², panels that have recently written weight guidelines are “ossified” and “refuse to accept” the implications of these findings, said Dr. Yusuf, professor of medicine at McMaster and executive director of the Population Health Research Institute.

The results of the analyses that Dr. Leong reported also showed that BMI paled as a prognosticator for survival when compared with two other assessments of weight: waist/hip ratio, and even more powerful prognostically, a novel measure developed for this analysis that calculates the ratio of hand-grip strength/body weight. Waist/hip ratio adds the dimension of the location of body fat rather than just the amount, and the ratio of grip strength/body weight assesses the contribution of muscle mass to overall weight, noted Dr. Leong. He reported an optimal waist/hip ratio for survival of 0.83 in women and 0.93 in men, and an optimal strength/weight ratio of 0.42 in women and 0.50 in men. This means that a man whose hand-grip strength (measured in kg) is half of the person’s body weight has the best prospect for survival.
 
The study used data collected in PURE (Prospective Urban Rural Epidemiology Study) on 142,410 people aged 35-70 years from any one of four high-income countries, 12 middle-income countries, and five low-income countries. The study excluded people who had at baseline known coronary artery disease, stroke, heart failure, or cancer, and the adjusted analysis controlled for age, sex, region, education, activity, alcohol and tobacco use, and the baseline prevalence of hypertension and diabetes. During follow-up, 9,712 of these people died.

The researchers saw a nadir for mortality among people with a BMI of 25-29 kg/m² for both cardiovascular and noncardiovascular deaths. In addition, the link between total mortality and BMI was strongest in the subgroup of people on one or more treatments aimed at preventing cardiovascular disease, while it essentially disappeared among people not receiving any cardiovascular disease preventive measures, highlighting that the relationship now identified depends on a context of overall cardiovascular disease risk reduction, Dr. Leong said. The results also showed a very clear, direct, linear relationship between higher BMI and both the incidence of diabetes and cardiovascular disease, as well as increased all-cause and noncardiovascular mortality among people with a BMI of less than 20 kg/m².

Dr. Yusuf discussed the results of the analysis in a video interview.

The PURE study has received partial funding from unrestricted grants from several drug companies. Dr. Leong has been an advisor to Ferring Pharmaceuticals and has been a speaker on behalf of Janssen. Dr. Yusuf had no disclosures.

[email protected]

This story was updated 9/19/2019.

PARIS – Middle-aged adults with a body mass index of 25-29 kg/m² had a significantly better adjusted survival during a median follow-up of nearly 10 years than did people with a “normal” body mass index of 20-24 kg/m² in a worldwide study of more than 140,000. This finding suggests the current, widely accepted definition of normal body mass index is wrong.*

Mitchel L. Zoler/MDedge News

The new findings suggest that the current definition of a “healthy” body mass index (BMI) “should be re-evaluated,” Darryl P. Leong, MBBS, said at the annual Congress of the European Society of Cardiology. The analysis also identified a BMI specifically of 27 kg/m² as associated with optimal survival among both women and men, “clearly outside the range of 20 to less than 25 kg/m² that is considered normal,” said Dr. Leong, a cardiologist at McMaster University and the Population Health Research Institute, both in Hamilton, Ont.

Dr. Leong cited three potential explanations for why the new study identified optimal survival with a BMI of 25 to less than 30 kg/m² among people who were 35-70 years old when they entered the study and were followed for a median of 9.5 years: The current study collected data and adjusted the results using a wider range of potential confounders than in prior studies, the data reflect the impact of contemporary interventions to reduce cardiovascular disease illness and death while past studies relied on data from earlier times when less cardiovascular disease protection occurred, and the current study included people from lower-income countries, although the finding is just as applicable to people who live in high-income countries, who were also included in the study population, noted Salim Yusuf, MBBS, principal investigator for the study.

A BMI of 20-24 kg/m² “is actually low and harmful,” noted Dr. Yusuf in an interview. Despite recent data consistently showing better survival among people with a BMI of 25-29 kg/m², panels that have recently written weight guidelines are “ossified” and “refuse to accept” the implications of these findings, said Dr. Yusuf, professor of medicine at McMaster and executive director of the Population Health Research Institute.

The results of the analyses that Dr. Leong reported also showed that BMI paled as a prognosticator for survival when compared with two other assessments of weight: waist/hip ratio, and even more powerful prognostically, a novel measure developed for this analysis that calculates the ratio of hand-grip strength/body weight. Waist/hip ratio adds the dimension of the location of body fat rather than just the amount, and the ratio of grip strength/body weight assesses the contribution of muscle mass to overall weight, noted Dr. Leong. He reported an optimal waist/hip ratio for survival of 0.83 in women and 0.93 in men, and an optimal strength/weight ratio of 0.42 in women and 0.50 in men. This means that a man whose hand-grip strength (measured in kg) is half of the person’s body weight has the best prospect for survival.
 
The study used data collected in PURE (Prospective Urban Rural Epidemiology Study) on 142,410 people aged 35-70 years from any one of four high-income countries, 12 middle-income countries, and five low-income countries. The study excluded people who had at baseline known coronary artery disease, stroke, heart failure, or cancer, and the adjusted analysis controlled for age, sex, region, education, activity, alcohol and tobacco use, and the baseline prevalence of hypertension and diabetes. During follow-up, 9,712 of these people died.

The researchers saw a nadir for mortality among people with a BMI of 25-29 kg/m² for both cardiovascular and noncardiovascular deaths. In addition, the link between total mortality and BMI was strongest in the subgroup of people on one or more treatments aimed at preventing cardiovascular disease, while it essentially disappeared among people not receiving any cardiovascular disease preventive measures, highlighting that the relationship now identified depends on a context of overall cardiovascular disease risk reduction, Dr. Leong said. The results also showed a very clear, direct, linear relationship between higher BMI and both the incidence of diabetes and cardiovascular disease, as well as increased all-cause and noncardiovascular mortality among people with a BMI of less than 20 kg/m².

Dr. Yusuf discussed the results of the analysis in a video interview.

The PURE study has received partial funding from unrestricted grants from several drug companies. Dr. Leong has been an advisor to Ferring Pharmaceuticals and has been a speaker on behalf of Janssen. Dr. Yusuf had no disclosures.

[email protected]

This story was updated 9/19/2019.

PARIS – Middle-aged adults with a body mass index of 25-29 kg/m² had a significantly better adjusted survival during a median follow-up of nearly 10 years than did people with a “normal” body mass index of 20-24 kg/m² in a worldwide study of more than 140,000. This finding suggests the current, widely accepted definition of normal body mass index is wrong.*

Mitchel L. Zoler/MDedge News

The new findings suggest that the current definition of a “healthy” body mass index (BMI) “should be re-evaluated,” Darryl P. Leong, MBBS, said at the annual Congress of the European Society of Cardiology. The analysis also identified a BMI specifically of 27 kg/m² as associated with optimal survival among both women and men, “clearly outside the range of 20 to less than 25 kg/m² that is considered normal,” said Dr. Leong, a cardiologist at McMaster University and the Population Health Research Institute, both in Hamilton, Ont.

Dr. Leong cited three potential explanations for why the new study identified optimal survival with a BMI of 25 to less than 30 kg/m² among people who were 35-70 years old when they entered the study and were followed for a median of 9.5 years: The current study collected data and adjusted the results using a wider range of potential confounders than in prior studies, the data reflect the impact of contemporary interventions to reduce cardiovascular disease illness and death while past studies relied on data from earlier times when less cardiovascular disease protection occurred, and the current study included people from lower-income countries, although the finding is just as applicable to people who live in high-income countries, who were also included in the study population, noted Salim Yusuf, MBBS, principal investigator for the study.

A BMI of 20-24 kg/m² “is actually low and harmful,” noted Dr. Yusuf in an interview. Despite recent data consistently showing better survival among people with a BMI of 25-29 kg/m², panels that have recently written weight guidelines are “ossified” and “refuse to accept” the implications of these findings, said Dr. Yusuf, professor of medicine at McMaster and executive director of the Population Health Research Institute.

The results of the analyses that Dr. Leong reported also showed that BMI paled as a prognosticator for survival when compared with two other assessments of weight: waist/hip ratio, and even more powerful prognostically, a novel measure developed for this analysis that calculates the ratio of hand-grip strength/body weight. Waist/hip ratio adds the dimension of the location of body fat rather than just the amount, and the ratio of grip strength/body weight assesses the contribution of muscle mass to overall weight, noted Dr. Leong. He reported an optimal waist/hip ratio for survival of 0.83 in women and 0.93 in men, and an optimal strength/weight ratio of 0.42 in women and 0.50 in men. This means that a man whose hand-grip strength (measured in kg) is half of the person’s body weight has the best prospect for survival.
 
The study used data collected in PURE (Prospective Urban Rural Epidemiology Study) on 142,410 people aged 35-70 years from any one of four high-income countries, 12 middle-income countries, and five low-income countries. The study excluded people who had at baseline known coronary artery disease, stroke, heart failure, or cancer, and the adjusted analysis controlled for age, sex, region, education, activity, alcohol and tobacco use, and the baseline prevalence of hypertension and diabetes. During follow-up, 9,712 of these people died.

The researchers saw a nadir for mortality among people with a BMI of 25-29 kg/m² for both cardiovascular and noncardiovascular deaths. In addition, the link between total mortality and BMI was strongest in the subgroup of people on one or more treatments aimed at preventing cardiovascular disease, while it essentially disappeared among people not receiving any cardiovascular disease preventive measures, highlighting that the relationship now identified depends on a context of overall cardiovascular disease risk reduction, Dr. Leong said. The results also showed a very clear, direct, linear relationship between higher BMI and both the incidence of diabetes and cardiovascular disease, as well as increased all-cause and noncardiovascular mortality among people with a BMI of less than 20 kg/m².

Dr. Yusuf discussed the results of the analysis in a video interview.

The PURE study has received partial funding from unrestricted grants from several drug companies. Dr. Leong has been an advisor to Ferring Pharmaceuticals and has been a speaker on behalf of Janssen. Dr. Yusuf had no disclosures.

[email protected]

This story was updated 9/19/2019.

PARIS – A small interfering RNA drug, inclisiran, safely halved LDL cholesterol levels in more than 800 patients in a phase 3, multicenter study, in a big step toward this drug coming onto the market and offering an alternative way to harness the potent cholesterol-lowering power of PCSK9 inhibition.

Mitchel L. Zoler/MDedge News

In the reported study – which enrolled patients with established cardiovascular disease, familial hypercholesterolemia, type 2 diabetes, or a high Framingham Risk Score – participants received inclisiran as a semiannual subcutaneous injection. The safe efficacy this produced showed the viability of a new way to deliver lipid-lowering therapy that guarantees compliance and is convenient for patients.

The prospect of lowering cholesterol with about the same potency as the monoclonal antibodies that block PCSK9 (proprotein convertase subtilisin/kexin type 9) activity but administered as a biannual injection “enables provider control over medication adherence, and may offer patients a meaningful new choice that is safe and convenient and has assured results,” Kausik K. Ray, MD, said at the annual congress of the European Society of Cardiology. The durable effect of the small interfering RNA (siRNA) agent “offers a huge advantage,” and “opens the field,” said Dr. Ray, a cardiologist and professor of public health at Imperial College, London.

He also highlighted the “excellent” safety profile seen in the 811 patients treated with inclisiran, compared with 804 patients in the study who received placebo. After four total injections of inclisiran spaced out over 450 days (about 15 months), the rate of treatment-emergent adverse events and serious events was virtually the same in the two treatment arms, and with no signal of inclisiran causing liver effects, renal or muscle injury, damage to blood components, or malignancy. The serial treatment with inclisiran that patients received – at baseline, 90, 270, and 450 days – produced no severe injection-site reactions, and transient mild or moderate injection-site reactions in just under 5% of patients.

Safety issues, such as more-severe injection-site reactions, thrombocytopenia, hepatotoxicity, and flu-like symptoms, plagued siRNA drugs during their earlier days of development, but more recently next-generation siRNA drugs with modified structures have produced much better safety performance, noted Richard C. Becker, MD, professor of medicine and director of the Heart, Lung, & Vascular Institute at the University of Cincinnati. The new-generation siRNAs such as inclisiran are “very well tolerated,” he said in an interview.

The Food and Drug Administration approved the first siRNA drug in August 2018, and in the year since then a few others have also come onto the U.S. market, Dr. Becker said.

Like other siRNA drugs, the activity of inclisiran comes from a short RNA segment that is antisense to a particular messenger RNA (mRNA) target. In the case of inclisiran, the target is the mRNA for the PCSK9 enzyme produced in hepatocytes, and that decreases the number of LDL cholesterol receptors on the cell’s surface. When the antisense RNA molecule encounters a PCSK9 mRNA, the two bind and the mRNA is then degraded by a normal cell process. This cuts the cell’s production of the PCSK9 protein, resulting in more LDL cholesterol receptors on the cell’s surface that pull more LDL cholesterol from the blood. The blocking of PCSK9 activity by inclisiran is roughly equivalent to the action of the PCSK9 monoclonal antibodies that have now been on the U.S. market for a few years. Also like other siRNA drugs, the RNA of inclisiran is packaged so that, once injected into a patient, the RNA molecules travel to the liver and enter hepatocytes, where they exert their activity.

“No one has concerns about inclisiran being able to lower LDL [cholesterol], and there have been no safety signals. The data we have seen so far look very reassuring, and in particular has been very safe for the liver,” commented Marc S. Sabatine, MD, professor of medicine at Harvard Medical School, Boston, who has led several studies involving PCSK9-targeted drugs and is helping to run ORION-4, a 15,000-patient study of inclisiran designed to assess the drug’s effect on clinical events. Results from ORION-4 are not expected until about 2024.

“The PCSK9 inhibitors in general have been a huge advance for patients, and the more kinds of drugs we have to target PCSK9, the better,” he said in an interview.

The study reported by Dr. Ray, ORION-11, enrolled 1,617 patients with high atherosclerotic disease risk at 70 sites in six European countries and South Africa. The study’s primary efficacy endpoint was reduction from baseline in LDL cholesterol both at 510 days (about 17 months) after the first dose and also throughout the 15-month period that started 3 months after the first dose. The average reduction seen after 510 days was 54%, compared with baseline, and the time-averaged reduction during the 15-month window examined was 50%, Dr. Ray said. The results also showed a consistent reduction in LDL cholesterol in virtually every patient treated with inclisiran.

Two other phase 3 studies of inclisiran with similar design have been completed, and the results will come out before the end of 2019, according to a statement from the Medicines Company, which is developing the drug. The statement also said that the company plans to file their data with the FDA for marketing approval for inclisiran before the end of 2019. In the recent past, the FDA has approved drugs for the indication of lowering LDL cholesterol before evidence is available to prove that the agent has benefits for reducing clinical events.

Future studies of inclisiran will explore the efficacy of a single annual injection of the drug as an approach to primary prevention of cardiovascular disease, Dr. Ray said.

ORION-11 was sponsored by the Medicines Company. Dr. Ray is a consultant to it and to several other companies. Dr. Becker had no relevant disclosures. Dr. Sabatine has received research support from the Medicines Company and several other companies, and has received personal fees from Anthos Therapeutics, Bristol-Myers Squibb, CVS Caremark, Daiichi Sankyo, DalCor Pharmaceuticals, Dyrnamix, and Ionis.

[email protected]

PARIS – A small interfering RNA drug, inclisiran, safely halved LDL cholesterol levels in more than 800 patients in a phase 3, multicenter study, in a big step toward this drug coming onto the market and offering an alternative way to harness the potent cholesterol-lowering power of PCSK9 inhibition.

Mitchel L. Zoler/MDedge News

In the reported study – which enrolled patients with established cardiovascular disease, familial hypercholesterolemia, type 2 diabetes, or a high Framingham Risk Score – participants received inclisiran as a semiannual subcutaneous injection. The safe efficacy this produced showed the viability of a new way to deliver lipid-lowering therapy that guarantees compliance and is convenient for patients.

The prospect of lowering cholesterol with about the same potency as the monoclonal antibodies that block PCSK9 (proprotein convertase subtilisin/kexin type 9) activity but administered as a biannual injection “enables provider control over medication adherence, and may offer patients a meaningful new choice that is safe and convenient and has assured results,” Kausik K. Ray, MD, said at the annual congress of the European Society of Cardiology. The durable effect of the small interfering RNA (siRNA) agent “offers a huge advantage,” and “opens the field,” said Dr. Ray, a cardiologist and professor of public health at Imperial College, London.

He also highlighted the “excellent” safety profile seen in the 811 patients treated with inclisiran, compared with 804 patients in the study who received placebo. After four total injections of inclisiran spaced out over 450 days (about 15 months), the rate of treatment-emergent adverse events and serious events was virtually the same in the two treatment arms, and with no signal of inclisiran causing liver effects, renal or muscle injury, damage to blood components, or malignancy. The serial treatment with inclisiran that patients received – at baseline, 90, 270, and 450 days – produced no severe injection-site reactions, and transient mild or moderate injection-site reactions in just under 5% of patients.

Safety issues, such as more-severe injection-site reactions, thrombocytopenia, hepatotoxicity, and flu-like symptoms, plagued siRNA drugs during their earlier days of development, but more recently next-generation siRNA drugs with modified structures have produced much better safety performance, noted Richard C. Becker, MD, professor of medicine and director of the Heart, Lung, & Vascular Institute at the University of Cincinnati. The new-generation siRNAs such as inclisiran are “very well tolerated,” he said in an interview.

The Food and Drug Administration approved the first siRNA drug in August 2018, and in the year since then a few others have also come onto the U.S. market, Dr. Becker said.

Like other siRNA drugs, the activity of inclisiran comes from a short RNA segment that is antisense to a particular messenger RNA (mRNA) target. In the case of inclisiran, the target is the mRNA for the PCSK9 enzyme produced in hepatocytes, and that decreases the number of LDL cholesterol receptors on the cell’s surface. When the antisense RNA molecule encounters a PCSK9 mRNA, the two bind and the mRNA is then degraded by a normal cell process. This cuts the cell’s production of the PCSK9 protein, resulting in more LDL cholesterol receptors on the cell’s surface that pull more LDL cholesterol from the blood. The blocking of PCSK9 activity by inclisiran is roughly equivalent to the action of the PCSK9 monoclonal antibodies that have now been on the U.S. market for a few years. Also like other siRNA drugs, the RNA of inclisiran is packaged so that, once injected into a patient, the RNA molecules travel to the liver and enter hepatocytes, where they exert their activity.

“No one has concerns about inclisiran being able to lower LDL [cholesterol], and there have been no safety signals. The data we have seen so far look very reassuring, and in particular has been very safe for the liver,” commented Marc S. Sabatine, MD, professor of medicine at Harvard Medical School, Boston, who has led several studies involving PCSK9-targeted drugs and is helping to run ORION-4, a 15,000-patient study of inclisiran designed to assess the drug’s effect on clinical events. Results from ORION-4 are not expected until about 2024.

“The PCSK9 inhibitors in general have been a huge advance for patients, and the more kinds of drugs we have to target PCSK9, the better,” he said in an interview.

The study reported by Dr. Ray, ORION-11, enrolled 1,617 patients with high atherosclerotic disease risk at 70 sites in six European countries and South Africa. The study’s primary efficacy endpoint was reduction from baseline in LDL cholesterol both at 510 days (about 17 months) after the first dose and also throughout the 15-month period that started 3 months after the first dose. The average reduction seen after 510 days was 54%, compared with baseline, and the time-averaged reduction during the 15-month window examined was 50%, Dr. Ray said. The results also showed a consistent reduction in LDL cholesterol in virtually every patient treated with inclisiran.

Two other phase 3 studies of inclisiran with similar design have been completed, and the results will come out before the end of 2019, according to a statement from the Medicines Company, which is developing the drug. The statement also said that the company plans to file their data with the FDA for marketing approval for inclisiran before the end of 2019. In the recent past, the FDA has approved drugs for the indication of lowering LDL cholesterol before evidence is available to prove that the agent has benefits for reducing clinical events.

Future studies of inclisiran will explore the efficacy of a single annual injection of the drug as an approach to primary prevention of cardiovascular disease, Dr. Ray said.

ORION-11 was sponsored by the Medicines Company. Dr. Ray is a consultant to it and to several other companies. Dr. Becker had no relevant disclosures. Dr. Sabatine has received research support from the Medicines Company and several other companies, and has received personal fees from Anthos Therapeutics, Bristol-Myers Squibb, CVS Caremark, Daiichi Sankyo, DalCor Pharmaceuticals, Dyrnamix, and Ionis.

[email protected]

PARIS – A small interfering RNA drug, inclisiran, safely halved LDL cholesterol levels in more than 800 patients in a phase 3, multicenter study, in a big step toward this drug coming onto the market and offering an alternative way to harness the potent cholesterol-lowering power of PCSK9 inhibition.

Mitchel L. Zoler/MDedge News

In the reported study – which enrolled patients with established cardiovascular disease, familial hypercholesterolemia, type 2 diabetes, or a high Framingham Risk Score – participants received inclisiran as a semiannual subcutaneous injection. The safe efficacy this produced showed the viability of a new way to deliver lipid-lowering therapy that guarantees compliance and is convenient for patients.

The prospect of lowering cholesterol with about the same potency as the monoclonal antibodies that block PCSK9 (proprotein convertase subtilisin/kexin type 9) activity but administered as a biannual injection “enables provider control over medication adherence, and may offer patients a meaningful new choice that is safe and convenient and has assured results,” Kausik K. Ray, MD, said at the annual congress of the European Society of Cardiology. The durable effect of the small interfering RNA (siRNA) agent “offers a huge advantage,” and “opens the field,” said Dr. Ray, a cardiologist and professor of public health at Imperial College, London.

He also highlighted the “excellent” safety profile seen in the 811 patients treated with inclisiran, compared with 804 patients in the study who received placebo. After four total injections of inclisiran spaced out over 450 days (about 15 months), the rate of treatment-emergent adverse events and serious events was virtually the same in the two treatment arms, and with no signal of inclisiran causing liver effects, renal or muscle injury, damage to blood components, or malignancy. The serial treatment with inclisiran that patients received – at baseline, 90, 270, and 450 days – produced no severe injection-site reactions, and transient mild or moderate injection-site reactions in just under 5% of patients.

Safety issues, such as more-severe injection-site reactions, thrombocytopenia, hepatotoxicity, and flu-like symptoms, plagued siRNA drugs during their earlier days of development, but more recently next-generation siRNA drugs with modified structures have produced much better safety performance, noted Richard C. Becker, MD, professor of medicine and director of the Heart, Lung, & Vascular Institute at the University of Cincinnati. The new-generation siRNAs such as inclisiran are “very well tolerated,” he said in an interview.

The Food and Drug Administration approved the first siRNA drug in August 2018, and in the year since then a few others have also come onto the U.S. market, Dr. Becker said.

Like other siRNA drugs, the activity of inclisiran comes from a short RNA segment that is antisense to a particular messenger RNA (mRNA) target. In the case of inclisiran, the target is the mRNA for the PCSK9 enzyme produced in hepatocytes, and that decreases the number of LDL cholesterol receptors on the cell’s surface. When the antisense RNA molecule encounters a PCSK9 mRNA, the two bind and the mRNA is then degraded by a normal cell process. This cuts the cell’s production of the PCSK9 protein, resulting in more LDL cholesterol receptors on the cell’s surface that pull more LDL cholesterol from the blood. The blocking of PCSK9 activity by inclisiran is roughly equivalent to the action of the PCSK9 monoclonal antibodies that have now been on the U.S. market for a few years. Also like other siRNA drugs, the RNA of inclisiran is packaged so that, once injected into a patient, the RNA molecules travel to the liver and enter hepatocytes, where they exert their activity.

“No one has concerns about inclisiran being able to lower LDL [cholesterol], and there have been no safety signals. The data we have seen so far look very reassuring, and in particular has been very safe for the liver,” commented Marc S. Sabatine, MD, professor of medicine at Harvard Medical School, Boston, who has led several studies involving PCSK9-targeted drugs and is helping to run ORION-4, a 15,000-patient study of inclisiran designed to assess the drug’s effect on clinical events. Results from ORION-4 are not expected until about 2024.

“The PCSK9 inhibitors in general have been a huge advance for patients, and the more kinds of drugs we have to target PCSK9, the better,” he said in an interview.

The study reported by Dr. Ray, ORION-11, enrolled 1,617 patients with high atherosclerotic disease risk at 70 sites in six European countries and South Africa. The study’s primary efficacy endpoint was reduction from baseline in LDL cholesterol both at 510 days (about 17 months) after the first dose and also throughout the 15-month period that started 3 months after the first dose. The average reduction seen after 510 days was 54%, compared with baseline, and the time-averaged reduction during the 15-month window examined was 50%, Dr. Ray said. The results also showed a consistent reduction in LDL cholesterol in virtually every patient treated with inclisiran.

Two other phase 3 studies of inclisiran with similar design have been completed, and the results will come out before the end of 2019, according to a statement from the Medicines Company, which is developing the drug. The statement also said that the company plans to file their data with the FDA for marketing approval for inclisiran before the end of 2019. In the recent past, the FDA has approved drugs for the indication of lowering LDL cholesterol before evidence is available to prove that the agent has benefits for reducing clinical events.

Future studies of inclisiran will explore the efficacy of a single annual injection of the drug as an approach to primary prevention of cardiovascular disease, Dr. Ray said.

ORION-11 was sponsored by the Medicines Company. Dr. Ray is a consultant to it and to several other companies. Dr. Becker had no relevant disclosures. Dr. Sabatine has received research support from the Medicines Company and several other companies, and has received personal fees from Anthos Therapeutics, Bristol-Myers Squibb, CVS Caremark, Daiichi Sankyo, DalCor Pharmaceuticals, Dyrnamix, and Ionis.

[email protected]

With the Food and Drug Administration’s approval of two different pairs of transcatheter aortic valve replacement systems for patients at low surgical risk, U.S. case volume for the procedure should markedly rise given that patients at low surgical risk form the largest risk subgroup among patients with aortic stenosis severe enough to warrant valve replacement.

Courtesy Dr Cleveland

But even as transcatheter aortic valve replacement (TAVR) now becomes the predominant approach for fixing severely stenotic aortic valves regardless of a patient’s risk level, the procedure remains less optimal than surgical aortic valve replacement (SAVR) in selected patients, putting an onus on clinicians to identify and alert patients for whom the transcatheter approach is questionable.

The anticipated surge in TAVR cases for low-risk patients after the FDA’s Aug. 16, 2019, decision will also likely lead to more hospitals offering TAVR. That development will test whether recently enacted rules from the Centers for Medicare & Medicaid Services on procedure-volume minimums for TAVR programs – at least 20 cases a year (or 40 within 2 years) at centers that also perform at least 300 percutaneous coronary interventions annually – lead to outcomes at lower-volume centers that come reasonably close to the outcomes at higher-volume programs for low-risk patients.

“The paradigm has definitely shifted from SAVR as the gold standard to TAVR as the primary treatment for aortic stenosis. This opens TAVR to the vast majority of patients with aortic stenosis,” roughly three-quarters of patients with aortic valve stenosis severe enough to need valve replacement, said Joseph C. Cleveland Jr., MD, a cardiothoracic surgeon and professor of surgery at the University of Colorado at Denver, Aurora.

University of Colorado Hospital

The actual, immediate increase in TAVR patients may not be quite as large as this fraction suggests. That’s in part because many patients in the low-risk category based on their surgical risk score already have been judged to have higher-risk features by heart-valve teams that has allowed such patients to undergo TAVR, said John D. Carroll, MD, professor of medicine and director of interventional cardiology at the University of Colorado.

For several years, U.S. rates of TAVR have exceeded SAVR, he noted, and in 2018 U.S. programs performed roughly 58,000 TAVR procedures and about 25,000 SAVRs, according to data collected by the Transcatheter Valve Therapy (TVT) Registry run by the Society of Thoracic Surgeons and the American College of Cardiology. Dr. Carroll is vice chair of the steering committee for this registry, which was mandated by the FDA in 2011 when the agency first allowed TAVR onto the U.S. market and is designed to capture every TAVR case performed in routine U.S. practice.

Despite this caveat, “there will be substantial growth in TAVR. Going forward, there will be more of a shift from SAVR to TAVR. That is what the results of the low-risk trials did,” Dr. Carroll predicted. In addition, the coming growth in TAVR numbers will stem from more than just low-risk patients whom a month ago would have undergone SAVR but now undergo TAVR instead. The availability of TAVR as an option for a wider range of patients should help boost public awareness that a nonsurgical way exists to treat severe aortic stenosis, plus the aging of baby boomers is on the verge of generating a substantial wave of new patients, a wave so high that Dr. Carroll called it a looming “tsunami” of patients needing TAVR.

How will low-risk TAVR affect lower-volume sites?

More TAVR patients will inevitably mean more U.S. sites offering the procedure, experts agreed. “We anticipate more low-volume programs,” Dr. Carroll said.

Bruce Jancin/Frontline Medical News

“Approval of TAVR for low-risk patients will result in a significant increase in the number of programs offering it. Approximately 1,100 U.S. programs offer SAVR, and as of now about 600 of these programs also offer TAVR. Health systems face the risk of losing patients if they don’t offer TAVR now that low-risk patients can be treated,” observed Sreekanth Vemulapalli, MD, a cardiologist at Duke University, Durham, N.C. who has run several studies using TVT Registry data and serves as liaison between the registry and its analytic center at Duke.

One of these studies, published earlier in 2019, showed that, among more than 96,000 registry patients who underwent transfemoral TAVR during 2015-2017 at 554 U.S. centers, those treated at sites that fell into the bottom quartile for case volume had an adjusted 30-day mortality rate that was 21% higher relative to patients treated at centers in the top quartile, a statistically significant difference (N Engl J Med. 2019 Jun 27;380[26]:2541-50). The absolute difference in adjusted 30-day mortality between the lowest and highest quartiles was 0.54%, roughly 1 additional death for every 200 patients. The TAVR centers in the lowest-volume quartile performed 5-36 cases/year, averaging 27 TAVRs/year; those in the highest quartile performed 86-371 TAVRs annually with an overall quartile average of 143 procedures/year.

Dr. Vemulapalli and others cautioned that TAVR case volume is currently serving as a surrogate, and imperfect, marker for program quality until TAVR programs generate enough data to allow a directly measured, risk-adjusted, outcome-driven assessment of performance. In the study he and his associates published in June, the 140 TAVR programs in the lowest-volume quartile showed a “high” level of variability in their adjusted mortality rates. Despite this limitation, the prospect that new TAVR programs will soon open to meet growing TAVR demand from low-risk patients poses the question of how these programs will perform during their start-up days (and possibly beyond), when case volumes may be light, especially if sites open in more remote sections of the United States.

“Will the real-world results of TAVR in low-risk patients match the fantastic results in the two low-risk TAVR trials?” wondered Dr. Carroll, referring to the PARTNER 3 (N Engl J Med. 2019 May 2;380[18]:1695-1705) and Evolut Low-Risk Patients trial (N Engl J Med. 2019 May 2;380[18]:1706-15). “It’s unknown whether a site just starting to do TAVRs will get the same results. The sites that participated in the low-risk trials were mostly high-volume sites.” On the other hand, TVT Registry data have shown that patients with surgical risk that was judged prohibitive, high, or intermediate all have had overall real-world outcomes that match what was seen in the relevant TAVR trials.

In addition, some experts view a modest drop in 30-day survival among patients treated at lower-volume TAVR sites as a reasonable trade-off for easier access for patients seeking this life-changing treatment.

“We need to ensure that patients have access to this treatment option,” said Catherine M. Otto, MD, professor of medicine and director of the Heart Valve Clinic at the University of Washington, Seattle. The potentially better outcomes produced at larger TAVR programs “need to be balanced against having a greater number of programs to ensure access for more patients and allow patients to be treated closer to home,” she said in an interview. She suggested that the potential exists to use telemedicine to link larger and more experienced TAVR programs with smaller and newer programs to help boost their performance.

“There is no perfect solution or metric to ensure high quality while also allowing for adequate access. As indications for TAVR expand we need to maintain vigilance and accountability as the therapy is dispersed to more patients at more centers,” said Brian R. Lindman, MD, medical director of the Structural Heat and Valve Center at Vanderbilt University, Nashville, Tenn. “We also need to insure that certain groups of patients have adequate access to this therapy. Adequate access to TAVR and high-quality clinical outcomes are both important goals.”

Plus, “the volume relationship may be less important,” in lower-risk patients, suggested Dr. Cleveland in an interview. Low-risk patients are younger and have fewer comorbidities and less vascular disease. “Low-volume centers should be able to treat these patients,” he said. Despite that, he personally supported the higher volume minimum for TAVR of 50 cases/year that the ACC, STS, and other U.S. professional societies recommended to CMS during public comment on the proposed rules. “We’ll see whether the increased access is worth this volume minimum.”

Who still gets SAVR?

Given the inherent attraction TAVR holds over SAVR for patients, heart-valve teams will need to convey the right message to patients who may be better served with surgical replacement despite the added trauma and recovery time it produces.

“The decision to perform TAVR or SAVR should now be based on a patient’s expected longevity as well as patient preferences and values, and not on the patient’s estimated surgical risk, except for the highest-risk patients in whom TAVR is recommended,” said Dr. Otto. A patient’s age, comorbidities, and overall life expectancy now move to center stage when deciding the TAVR or SAVR question, along with individual anatomic considerations, the possible need for concurrent procedures, and of course what the patient prefers including their willingness and ability to remain on lifelong anticoagulation if they receive a durable mechanical valve. Dr. Otto outlined this new landscape of the heart-valve team’s decision making process in an editorial she recently published (N Engl J Med. 2019 May 2;380[18]: 1769-70) that accompanied publication of PARTNER 3 and the Evolut Low-Risk Patients trial.

“For some patients there will be clear benefit from one approach, but for many patients, particularly those at low surgical risk, both TAVR and SAVR are technically feasible. For these patients it’s essential that the heart-valve team provide unbiased information to guide patients,” Dr. Otto said. The ideal person to provide this unbiased presentation of the pros and cons would be a cardiologist experienced with valve disease but not actively involved in performing valve-replacement procedures.

A big issue younger patients must confront is what remains unknown about long-term durability of TAVR valves. Dr. Otto called this “the most important missing piece of information. We only have robust data out to about 5 years. If TAVR valve will be durable for 15-20 years, then TAVR will become preferred even in younger patients.”

Even after TAVR became available to intermediate-risk patients in 2016, the median age of U.S. patients undergoing TAVR hardly budged, and has recently stood at about 81 years, Dr. Carroll noted. “With low-risk patients, we expect to see this change,” as more patients now who are in their 70s, 60s, and younger start to routinely undergo TAVR. As more younger patients with life expectancies on the order of 30 years consider TAVR, issues of valve durability “enter the discussion,” he said. “We need data to 10, 15 years,” and in its low-risk approval the FDA mandated manufacturers to follow these patients for at least 10 years. Although valve-in-valve replacement of failed TAVR valves is an option, it’s not always a smooth fix with the potential for prosthesis-patient mismatch (J Am Coll Cardiol. 2018 Dec 4;72[22]:2701-11) and resulting hemodynamic problems, Dr. Carroll said.

Bicuspid-valve replacement with TAVR is another big unknown, largely because these patients were excluded from the TAVR trials. A recently published analysis of the 2,726 patients with a bicuspid aortic valve who underwent TAVR anyway in routine U.S. practice between June 2015 and November 2018 and were in the TVT Registry (about 3% of all TAVR patients during this period) showed that these patients had similar mortality, compared with the tricuspid-valve patients, but a significantly increased stroke rate (JAMA. 2019 Jun 11;321[22]:2193-202). The authors concluded that a prospective, randomized study of TAVR, compared with SAVR, is needed for these patients, and many others in the field agree.

As availability of TAVR grows and public awareness increases, heart-valve teams may find it challenging sometimes to help patients understand the upsides of SAVR for their individual clinical needs when TAVR is superficially so much more attractive.

“The desire to avoid the prolonged hospitalization and recovery from SAVR is a huge driver of patient preference,” noted Dr. Carroll.

“It’s hard to tell a 55 year old to think about another procedure they may need when they are 65 or 70 if they undergo TAVR now rather than SAVR. They don’t want open-heart surgery; I hear that all the time,” Dr. Cleveland said. “If I were a 55-year-old aortic valve patient I’d strongly consider TAVR, too.”

Financial consideration at the site performing the interventions can also be a factor. “Differential costs and payments associated with SAVR and TAVR create different financial incentives for health systems between these two procedures,” noted Dr. Vemulapalli. “There likely needs to be a system that creates equal incentives to do SAVR or TAVR so that the decision between them can come down to just the patient and heart-valve team. We need further data and decision aids to help better define which patients will likely do better with SAVR and which with TAVR.”

What now?

Since the first large TAVR trials started in 2007, their main thrust has been to prove the efficacy and safety of TAVR in patients at sequentially less risk of undergoing SAVR. Now that this series of comparisons has ended, where will TAVR research turn its attention?

In addition to the big outstanding issues of TAVR-valve long-term durability, and the efficacy and safety of TAVR for replacing bicuspid valves, other big questions and issues loom. They include the optimal anticoagulant regimen for preventing leaflet thrombosis, reducing the need for pacemakers, reducing strokes, the applicability of TAVR to patients with less severe aortic stenosis, the impact of treating severe but asymptomatic aortic valve obstruction, optimizing valve-in-valve outcomes, and further improvements to valve design, hemodynamics, and delivery. In short, the question of TAVR’s suitability for patients regardless of their surgical risk may have now been answered, but many questions remain about the best way to use and to optimize this technology.

Dr. Cleveland and Dr. Carroll have participated in TAVR trials but had no personal financial disclosures. Dr. Otto had no disclosures. Dr. Vemulapalli has received personal fees from Janssen, Novella, Premiere, and Zafgen, and research funding from Boston Scientific and Abbott Vascular. Dr. Lindman has been a consultant to Medtronic, has served as an advisor to Roche, and has received research funding from Edwards Lifesciences.

[email protected]

With the Food and Drug Administration’s approval of two different pairs of transcatheter aortic valve replacement systems for patients at low surgical risk, U.S. case volume for the procedure should markedly rise given that patients at low surgical risk form the largest risk subgroup among patients with aortic stenosis severe enough to warrant valve replacement.

Courtesy Dr Cleveland

But even as transcatheter aortic valve replacement (TAVR) now becomes the predominant approach for fixing severely stenotic aortic valves regardless of a patient’s risk level, the procedure remains less optimal than surgical aortic valve replacement (SAVR) in selected patients, putting an onus on clinicians to identify and alert patients for whom the transcatheter approach is questionable.

The anticipated surge in TAVR cases for low-risk patients after the FDA’s Aug. 16, 2019, decision will also likely lead to more hospitals offering TAVR. That development will test whether recently enacted rules from the Centers for Medicare & Medicaid Services on procedure-volume minimums for TAVR programs – at least 20 cases a year (or 40 within 2 years) at centers that also perform at least 300 percutaneous coronary interventions annually – lead to outcomes at lower-volume centers that come reasonably close to the outcomes at higher-volume programs for low-risk patients.

“The paradigm has definitely shifted from SAVR as the gold standard to TAVR as the primary treatment for aortic stenosis. This opens TAVR to the vast majority of patients with aortic stenosis,” roughly three-quarters of patients with aortic valve stenosis severe enough to need valve replacement, said Joseph C. Cleveland Jr., MD, a cardiothoracic surgeon and professor of surgery at the University of Colorado at Denver, Aurora.

University of Colorado Hospital

The actual, immediate increase in TAVR patients may not be quite as large as this fraction suggests. That’s in part because many patients in the low-risk category based on their surgical risk score already have been judged to have higher-risk features by heart-valve teams that has allowed such patients to undergo TAVR, said John D. Carroll, MD, professor of medicine and director of interventional cardiology at the University of Colorado.

For several years, U.S. rates of TAVR have exceeded SAVR, he noted, and in 2018 U.S. programs performed roughly 58,000 TAVR procedures and about 25,000 SAVRs, according to data collected by the Transcatheter Valve Therapy (TVT) Registry run by the Society of Thoracic Surgeons and the American College of Cardiology. Dr. Carroll is vice chair of the steering committee for this registry, which was mandated by the FDA in 2011 when the agency first allowed TAVR onto the U.S. market and is designed to capture every TAVR case performed in routine U.S. practice.

Despite this caveat, “there will be substantial growth in TAVR. Going forward, there will be more of a shift from SAVR to TAVR. That is what the results of the low-risk trials did,” Dr. Carroll predicted. In addition, the coming growth in TAVR numbers will stem from more than just low-risk patients whom a month ago would have undergone SAVR but now undergo TAVR instead. The availability of TAVR as an option for a wider range of patients should help boost public awareness that a nonsurgical way exists to treat severe aortic stenosis, plus the aging of baby boomers is on the verge of generating a substantial wave of new patients, a wave so high that Dr. Carroll called it a looming “tsunami” of patients needing TAVR.

How will low-risk TAVR affect lower-volume sites?

More TAVR patients will inevitably mean more U.S. sites offering the procedure, experts agreed. “We anticipate more low-volume programs,” Dr. Carroll said.

Bruce Jancin/Frontline Medical News

“Approval of TAVR for low-risk patients will result in a significant increase in the number of programs offering it. Approximately 1,100 U.S. programs offer SAVR, and as of now about 600 of these programs also offer TAVR. Health systems face the risk of losing patients if they don’t offer TAVR now that low-risk patients can be treated,” observed Sreekanth Vemulapalli, MD, a cardiologist at Duke University, Durham, N.C. who has run several studies using TVT Registry data and serves as liaison between the registry and its analytic center at Duke.

One of these studies, published earlier in 2019, showed that, among more than 96,000 registry patients who underwent transfemoral TAVR during 2015-2017 at 554 U.S. centers, those treated at sites that fell into the bottom quartile for case volume had an adjusted 30-day mortality rate that was 21% higher relative to patients treated at centers in the top quartile, a statistically significant difference (N Engl J Med. 2019 Jun 27;380[26]:2541-50). The absolute difference in adjusted 30-day mortality between the lowest and highest quartiles was 0.54%, roughly 1 additional death for every 200 patients. The TAVR centers in the lowest-volume quartile performed 5-36 cases/year, averaging 27 TAVRs/year; those in the highest quartile performed 86-371 TAVRs annually with an overall quartile average of 143 procedures/year.

Dr. Vemulapalli and others cautioned that TAVR case volume is currently serving as a surrogate, and imperfect, marker for program quality until TAVR programs generate enough data to allow a directly measured, risk-adjusted, outcome-driven assessment of performance. In the study he and his associates published in June, the 140 TAVR programs in the lowest-volume quartile showed a “high” level of variability in their adjusted mortality rates. Despite this limitation, the prospect that new TAVR programs will soon open to meet growing TAVR demand from low-risk patients poses the question of how these programs will perform during their start-up days (and possibly beyond), when case volumes may be light, especially if sites open in more remote sections of the United States.

“Will the real-world results of TAVR in low-risk patients match the fantastic results in the two low-risk TAVR trials?” wondered Dr. Carroll, referring to the PARTNER 3 (N Engl J Med. 2019 May 2;380[18]:1695-1705) and Evolut Low-Risk Patients trial (N Engl J Med. 2019 May 2;380[18]:1706-15). “It’s unknown whether a site just starting to do TAVRs will get the same results. The sites that participated in the low-risk trials were mostly high-volume sites.” On the other hand, TVT Registry data have shown that patients with surgical risk that was judged prohibitive, high, or intermediate all have had overall real-world outcomes that match what was seen in the relevant TAVR trials.

In addition, some experts view a modest drop in 30-day survival among patients treated at lower-volume TAVR sites as a reasonable trade-off for easier access for patients seeking this life-changing treatment.

“We need to ensure that patients have access to this treatment option,” said Catherine M. Otto, MD, professor of medicine and director of the Heart Valve Clinic at the University of Washington, Seattle. The potentially better outcomes produced at larger TAVR programs “need to be balanced against having a greater number of programs to ensure access for more patients and allow patients to be treated closer to home,” she said in an interview. She suggested that the potential exists to use telemedicine to link larger and more experienced TAVR programs with smaller and newer programs to help boost their performance.

“There is no perfect solution or metric to ensure high quality while also allowing for adequate access. As indications for TAVR expand we need to maintain vigilance and accountability as the therapy is dispersed to more patients at more centers,” said Brian R. Lindman, MD, medical director of the Structural Heat and Valve Center at Vanderbilt University, Nashville, Tenn. “We also need to insure that certain groups of patients have adequate access to this therapy. Adequate access to TAVR and high-quality clinical outcomes are both important goals.”

Plus, “the volume relationship may be less important,” in lower-risk patients, suggested Dr. Cleveland in an interview. Low-risk patients are younger and have fewer comorbidities and less vascular disease. “Low-volume centers should be able to treat these patients,” he said. Despite that, he personally supported the higher volume minimum for TAVR of 50 cases/year that the ACC, STS, and other U.S. professional societies recommended to CMS during public comment on the proposed rules. “We’ll see whether the increased access is worth this volume minimum.”

Who still gets SAVR?

Given the inherent attraction TAVR holds over SAVR for patients, heart-valve teams will need to convey the right message to patients who may be better served with surgical replacement despite the added trauma and recovery time it produces.

“The decision to perform TAVR or SAVR should now be based on a patient’s expected longevity as well as patient preferences and values, and not on the patient’s estimated surgical risk, except for the highest-risk patients in whom TAVR is recommended,” said Dr. Otto. A patient’s age, comorbidities, and overall life expectancy now move to center stage when deciding the TAVR or SAVR question, along with individual anatomic considerations, the possible need for concurrent procedures, and of course what the patient prefers including their willingness and ability to remain on lifelong anticoagulation if they receive a durable mechanical valve. Dr. Otto outlined this new landscape of the heart-valve team’s decision making process in an editorial she recently published (N Engl J Med. 2019 May 2;380[18]: 1769-70) that accompanied publication of PARTNER 3 and the Evolut Low-Risk Patients trial.

“For some patients there will be clear benefit from one approach, but for many patients, particularly those at low surgical risk, both TAVR and SAVR are technically feasible. For these patients it’s essential that the heart-valve team provide unbiased information to guide patients,” Dr. Otto said. The ideal person to provide this unbiased presentation of the pros and cons would be a cardiologist experienced with valve disease but not actively involved in performing valve-replacement procedures.

A big issue younger patients must confront is what remains unknown about long-term durability of TAVR valves. Dr. Otto called this “the most important missing piece of information. We only have robust data out to about 5 years. If TAVR valve will be durable for 15-20 years, then TAVR will become preferred even in younger patients.”

Even after TAVR became available to intermediate-risk patients in 2016, the median age of U.S. patients undergoing TAVR hardly budged, and has recently stood at about 81 years, Dr. Carroll noted. “With low-risk patients, we expect to see this change,” as more patients now who are in their 70s, 60s, and younger start to routinely undergo TAVR. As more younger patients with life expectancies on the order of 30 years consider TAVR, issues of valve durability “enter the discussion,” he said. “We need data to 10, 15 years,” and in its low-risk approval the FDA mandated manufacturers to follow these patients for at least 10 years. Although valve-in-valve replacement of failed TAVR valves is an option, it’s not always a smooth fix with the potential for prosthesis-patient mismatch (J Am Coll Cardiol. 2018 Dec 4;72[22]:2701-11) and resulting hemodynamic problems, Dr. Carroll said.

Bicuspid-valve replacement with TAVR is another big unknown, largely because these patients were excluded from the TAVR trials. A recently published analysis of the 2,726 patients with a bicuspid aortic valve who underwent TAVR anyway in routine U.S. practice between June 2015 and November 2018 and were in the TVT Registry (about 3% of all TAVR patients during this period) showed that these patients had similar mortality, compared with the tricuspid-valve patients, but a significantly increased stroke rate (JAMA. 2019 Jun 11;321[22]:2193-202). The authors concluded that a prospective, randomized study of TAVR, compared with SAVR, is needed for these patients, and many others in the field agree.

As availability of TAVR grows and public awareness increases, heart-valve teams may find it challenging sometimes to help patients understand the upsides of SAVR for their individual clinical needs when TAVR is superficially so much more attractive.

“The desire to avoid the prolonged hospitalization and recovery from SAVR is a huge driver of patient preference,” noted Dr. Carroll.

“It’s hard to tell a 55 year old to think about another procedure they may need when they are 65 or 70 if they undergo TAVR now rather than SAVR. They don’t want open-heart surgery; I hear that all the time,” Dr. Cleveland said. “If I were a 55-year-old aortic valve patient I’d strongly consider TAVR, too.”

Financial consideration at the site performing the interventions can also be a factor. “Differential costs and payments associated with SAVR and TAVR create different financial incentives for health systems between these two procedures,” noted Dr. Vemulapalli. “There likely needs to be a system that creates equal incentives to do SAVR or TAVR so that the decision between them can come down to just the patient and heart-valve team. We need further data and decision aids to help better define which patients will likely do better with SAVR and which with TAVR.”

What now?

Since the first large TAVR trials started in 2007, their main thrust has been to prove the efficacy and safety of TAVR in patients at sequentially less risk of undergoing SAVR. Now that this series of comparisons has ended, where will TAVR research turn its attention?

In addition to the big outstanding issues of TAVR-valve long-term durability, and the efficacy and safety of TAVR for replacing bicuspid valves, other big questions and issues loom. They include the optimal anticoagulant regimen for preventing leaflet thrombosis, reducing the need for pacemakers, reducing strokes, the applicability of TAVR to patients with less severe aortic stenosis, the impact of treating severe but asymptomatic aortic valve obstruction, optimizing valve-in-valve outcomes, and further improvements to valve design, hemodynamics, and delivery. In short, the question of TAVR’s suitability for patients regardless of their surgical risk may have now been answered, but many questions remain about the best way to use and to optimize this technology.

Dr. Cleveland and Dr. Carroll have participated in TAVR trials but had no personal financial disclosures. Dr. Otto had no disclosures. Dr. Vemulapalli has received personal fees from Janssen, Novella, Premiere, and Zafgen, and research funding from Boston Scientific and Abbott Vascular. Dr. Lindman has been a consultant to Medtronic, has served as an advisor to Roche, and has received research funding from Edwards Lifesciences.

[email protected]

With the Food and Drug Administration’s approval of two different pairs of transcatheter aortic valve replacement systems for patients at low surgical risk, U.S. case volume for the procedure should markedly rise given that patients at low surgical risk form the largest risk subgroup among patients with aortic stenosis severe enough to warrant valve replacement.

Courtesy Dr Cleveland

But even as transcatheter aortic valve replacement (TAVR) now becomes the predominant approach for fixing severely stenotic aortic valves regardless of a patient’s risk level, the procedure remains less optimal than surgical aortic valve replacement (SAVR) in selected patients, putting an onus on clinicians to identify and alert patients for whom the transcatheter approach is questionable.

The anticipated surge in TAVR cases for low-risk patients after the FDA’s Aug. 16, 2019, decision will also likely lead to more hospitals offering TAVR. That development will test whether recently enacted rules from the Centers for Medicare & Medicaid Services on procedure-volume minimums for TAVR programs – at least 20 cases a year (or 40 within 2 years) at centers that also perform at least 300 percutaneous coronary interventions annually – lead to outcomes at lower-volume centers that come reasonably close to the outcomes at higher-volume programs for low-risk patients.

“The paradigm has definitely shifted from SAVR as the gold standard to TAVR as the primary treatment for aortic stenosis. This opens TAVR to the vast majority of patients with aortic stenosis,” roughly three-quarters of patients with aortic valve stenosis severe enough to need valve replacement, said Joseph C. Cleveland Jr., MD, a cardiothoracic surgeon and professor of surgery at the University of Colorado at Denver, Aurora.

University of Colorado Hospital

The actual, immediate increase in TAVR patients may not be quite as large as this fraction suggests. That’s in part because many patients in the low-risk category based on their surgical risk score already have been judged to have higher-risk features by heart-valve teams that has allowed such patients to undergo TAVR, said John D. Carroll, MD, professor of medicine and director of interventional cardiology at the University of Colorado.

For several years, U.S. rates of TAVR have exceeded SAVR, he noted, and in 2018 U.S. programs performed roughly 58,000 TAVR procedures and about 25,000 SAVRs, according to data collected by the Transcatheter Valve Therapy (TVT) Registry run by the Society of Thoracic Surgeons and the American College of Cardiology. Dr. Carroll is vice chair of the steering committee for this registry, which was mandated by the FDA in 2011 when the agency first allowed TAVR onto the U.S. market and is designed to capture every TAVR case performed in routine U.S. practice.

Despite this caveat, “there will be substantial growth in TAVR. Going forward, there will be more of a shift from SAVR to TAVR. That is what the results of the low-risk trials did,” Dr. Carroll predicted. In addition, the coming growth in TAVR numbers will stem from more than just low-risk patients whom a month ago would have undergone SAVR but now undergo TAVR instead. The availability of TAVR as an option for a wider range of patients should help boost public awareness that a nonsurgical way exists to treat severe aortic stenosis, plus the aging of baby boomers is on the verge of generating a substantial wave of new patients, a wave so high that Dr. Carroll called it a looming “tsunami” of patients needing TAVR.

How will low-risk TAVR affect lower-volume sites?

More TAVR patients will inevitably mean more U.S. sites offering the procedure, experts agreed. “We anticipate more low-volume programs,” Dr. Carroll said.

Bruce Jancin/Frontline Medical News

“Approval of TAVR for low-risk patients will result in a significant increase in the number of programs offering it. Approximately 1,100 U.S. programs offer SAVR, and as of now about 600 of these programs also offer TAVR. Health systems face the risk of losing patients if they don’t offer TAVR now that low-risk patients can be treated,” observed Sreekanth Vemulapalli, MD, a cardiologist at Duke University, Durham, N.C. who has run several studies using TVT Registry data and serves as liaison between the registry and its analytic center at Duke.

One of these studies, published earlier in 2019, showed that, among more than 96,000 registry patients who underwent transfemoral TAVR during 2015-2017 at 554 U.S. centers, those treated at sites that fell into the bottom quartile for case volume had an adjusted 30-day mortality rate that was 21% higher relative to patients treated at centers in the top quartile, a statistically significant difference (N Engl J Med. 2019 Jun 27;380[26]:2541-50). The absolute difference in adjusted 30-day mortality between the lowest and highest quartiles was 0.54%, roughly 1 additional death for every 200 patients. The TAVR centers in the lowest-volume quartile performed 5-36 cases/year, averaging 27 TAVRs/year; those in the highest quartile performed 86-371 TAVRs annually with an overall quartile average of 143 procedures/year.

Dr. Vemulapalli and others cautioned that TAVR case volume is currently serving as a surrogate, and imperfect, marker for program quality until TAVR programs generate enough data to allow a directly measured, risk-adjusted, outcome-driven assessment of performance. In the study he and his associates published in June, the 140 TAVR programs in the lowest-volume quartile showed a “high” level of variability in their adjusted mortality rates. Despite this limitation, the prospect that new TAVR programs will soon open to meet growing TAVR demand from low-risk patients poses the question of how these programs will perform during their start-up days (and possibly beyond), when case volumes may be light, especially if sites open in more remote sections of the United States.

“Will the real-world results of TAVR in low-risk patients match the fantastic results in the two low-risk TAVR trials?” wondered Dr. Carroll, referring to the PARTNER 3 (N Engl J Med. 2019 May 2;380[18]:1695-1705) and Evolut Low-Risk Patients trial (N Engl J Med. 2019 May 2;380[18]:1706-15). “It’s unknown whether a site just starting to do TAVRs will get the same results. The sites that participated in the low-risk trials were mostly high-volume sites.” On the other hand, TVT Registry data have shown that patients with surgical risk that was judged prohibitive, high, or intermediate all have had overall real-world outcomes that match what was seen in the relevant TAVR trials.

In addition, some experts view a modest drop in 30-day survival among patients treated at lower-volume TAVR sites as a reasonable trade-off for easier access for patients seeking this life-changing treatment.

“We need to ensure that patients have access to this treatment option,” said Catherine M. Otto, MD, professor of medicine and director of the Heart Valve Clinic at the University of Washington, Seattle. The potentially better outcomes produced at larger TAVR programs “need to be balanced against having a greater number of programs to ensure access for more patients and allow patients to be treated closer to home,” she said in an interview. She suggested that the potential exists to use telemedicine to link larger and more experienced TAVR programs with smaller and newer programs to help boost their performance.

“There is no perfect solution or metric to ensure high quality while also allowing for adequate access. As indications for TAVR expand we need to maintain vigilance and accountability as the therapy is dispersed to more patients at more centers,” said Brian R. Lindman, MD, medical director of the Structural Heat and Valve Center at Vanderbilt University, Nashville, Tenn. “We also need to insure that certain groups of patients have adequate access to this therapy. Adequate access to TAVR and high-quality clinical outcomes are both important goals.”

Plus, “the volume relationship may be less important,” in lower-risk patients, suggested Dr. Cleveland in an interview. Low-risk patients are younger and have fewer comorbidities and less vascular disease. “Low-volume centers should be able to treat these patients,” he said. Despite that, he personally supported the higher volume minimum for TAVR of 50 cases/year that the ACC, STS, and other U.S. professional societies recommended to CMS during public comment on the proposed rules. “We’ll see whether the increased access is worth this volume minimum.”

Who still gets SAVR?

Given the inherent attraction TAVR holds over SAVR for patients, heart-valve teams will need to convey the right message to patients who may be better served with surgical replacement despite the added trauma and recovery time it produces.

“The decision to perform TAVR or SAVR should now be based on a patient’s expected longevity as well as patient preferences and values, and not on the patient’s estimated surgical risk, except for the highest-risk patients in whom TAVR is recommended,” said Dr. Otto. A patient’s age, comorbidities, and overall life expectancy now move to center stage when deciding the TAVR or SAVR question, along with individual anatomic considerations, the possible need for concurrent procedures, and of course what the patient prefers including their willingness and ability to remain on lifelong anticoagulation if they receive a durable mechanical valve. Dr. Otto outlined this new landscape of the heart-valve team’s decision making process in an editorial she recently published (N Engl J Med. 2019 May 2;380[18]: 1769-70) that accompanied publication of PARTNER 3 and the Evolut Low-Risk Patients trial.

“For some patients there will be clear benefit from one approach, but for many patients, particularly those at low surgical risk, both TAVR and SAVR are technically feasible. For these patients it’s essential that the heart-valve team provide unbiased information to guide patients,” Dr. Otto said. The ideal person to provide this unbiased presentation of the pros and cons would be a cardiologist experienced with valve disease but not actively involved in performing valve-replacement procedures.

A big issue younger patients must confront is what remains unknown about long-term durability of TAVR valves. Dr. Otto called this “the most important missing piece of information. We only have robust data out to about 5 years. If TAVR valve will be durable for 15-20 years, then TAVR will become preferred even in younger patients.”

Even after TAVR became available to intermediate-risk patients in 2016, the median age of U.S. patients undergoing TAVR hardly budged, and has recently stood at about 81 years, Dr. Carroll noted. “With low-risk patients, we expect to see this change,” as more patients now who are in their 70s, 60s, and younger start to routinely undergo TAVR. As more younger patients with life expectancies on the order of 30 years consider TAVR, issues of valve durability “enter the discussion,” he said. “We need data to 10, 15 years,” and in its low-risk approval the FDA mandated manufacturers to follow these patients for at least 10 years. Although valve-in-valve replacement of failed TAVR valves is an option, it’s not always a smooth fix with the potential for prosthesis-patient mismatch (J Am Coll Cardiol. 2018 Dec 4;72[22]:2701-11) and resulting hemodynamic problems, Dr. Carroll said.

Bicuspid-valve replacement with TAVR is another big unknown, largely because these patients were excluded from the TAVR trials. A recently published analysis of the 2,726 patients with a bicuspid aortic valve who underwent TAVR anyway in routine U.S. practice between June 2015 and November 2018 and were in the TVT Registry (about 3% of all TAVR patients during this period) showed that these patients had similar mortality, compared with the tricuspid-valve patients, but a significantly increased stroke rate (JAMA. 2019 Jun 11;321[22]:2193-202). The authors concluded that a prospective, randomized study of TAVR, compared with SAVR, is needed for these patients, and many others in the field agree.

As availability of TAVR grows and public awareness increases, heart-valve teams may find it challenging sometimes to help patients understand the upsides of SAVR for their individual clinical needs when TAVR is superficially so much more attractive.

“The desire to avoid the prolonged hospitalization and recovery from SAVR is a huge driver of patient preference,” noted Dr. Carroll.

“It’s hard to tell a 55 year old to think about another procedure they may need when they are 65 or 70 if they undergo TAVR now rather than SAVR. They don’t want open-heart surgery; I hear that all the time,” Dr. Cleveland said. “If I were a 55-year-old aortic valve patient I’d strongly consider TAVR, too.”

Financial consideration at the site performing the interventions can also be a factor. “Differential costs and payments associated with SAVR and TAVR create different financial incentives for health systems between these two procedures,” noted Dr. Vemulapalli. “There likely needs to be a system that creates equal incentives to do SAVR or TAVR so that the decision between them can come down to just the patient and heart-valve team. We need further data and decision aids to help better define which patients will likely do better with SAVR and which with TAVR.”

What now?

Since the first large TAVR trials started in 2007, their main thrust has been to prove the efficacy and safety of TAVR in patients at sequentially less risk of undergoing SAVR. Now that this series of comparisons has ended, where will TAVR research turn its attention?

In addition to the big outstanding issues of TAVR-valve long-term durability, and the efficacy and safety of TAVR for replacing bicuspid valves, other big questions and issues loom. They include the optimal anticoagulant regimen for preventing leaflet thrombosis, reducing the need for pacemakers, reducing strokes, the applicability of TAVR to patients with less severe aortic stenosis, the impact of treating severe but asymptomatic aortic valve obstruction, optimizing valve-in-valve outcomes, and further improvements to valve design, hemodynamics, and delivery. In short, the question of TAVR’s suitability for patients regardless of their surgical risk may have now been answered, but many questions remain about the best way to use and to optimize this technology.

Dr. Cleveland and Dr. Carroll have participated in TAVR trials but had no personal financial disclosures. Dr. Otto had no disclosures. Dr. Vemulapalli has received personal fees from Janssen, Novella, Premiere, and Zafgen, and research funding from Boston Scientific and Abbott Vascular. Dr. Lindman has been a consultant to Medtronic, has served as an advisor to Roche, and has received research funding from Edwards Lifesciences.

[email protected]

PHILADELPHIA – The oral, small molecule, calcitonin gene-related peptide receptor antagonist ubrogepant, currently under regulatory review for approval as a treatment for acute migraine headache, was as effective for migraine relief in patients with a history of triptan ineffectiveness as it was in patients for whom triptans had been effective, based on a post hoc analysis of data collected from 1,798 patients enrolled in two phase 3 trials.

Mitchel L. Zoler/MDedge News

In the roughly one-quarter of all patients who had a clinical history consistent with triptan ineffectiveness, one 50-mg dose of ubrogepant led to pain freedom 2 hours after treatment in 16% of patients, compared with a response rate of 8% in placebo-treated patients. Ubrogepant’s effectiveness rate that was about the same as seen in patients with a history of triptan effectiveness, who were about 37% of the study population, Susan Hutchinson, MD, said at the annual meeting of the American Headache Society.

Among those with a history of triptan effectiveness, 20% were pain free after 2 hours, compared with 11% of placebo-treated controls, said Dr. Hutchinson, a family physician and headache specialist who practices in Irvine, Calif. Both of these between-group differences were statistically significant. The remaining patients included in the analysis had no triptan history, and among these patients a single, 50-mg dose of ubrogepant produced pain freedom at 2 hours in 24% of patients, versus an 18% response in placebo-treated controls, a difference that fell short of statistical significance.

The analysis Dr. Hutchinson reported came from data collected in two pivotal trials of ubrogepant for treatment of an acute migraine headache, the ACHIEVE I and ACHIEVE II trials, which together randomized more than 2,600 migraine patients eligible for the study’s modified intention-to-treat analysis, and 1,798 patients from that analysis who received a 50-mg dose of ubrogepant or placebo. In March 2019, the company developing ubrogepant, Allergan, announced that the Food and Drug Administration had accepted the company’s application for marketing approval of ubrogepant as a treatment for acute migraine largely based on data from ACHIEVE I and ACHIEVE II.

The researchers defined a history of triptan ineffectiveness as a patient who never used a triptan because of a warning, precaution, or contraindication, a patient who recently used triptans but did not achieve pain freedom within 2 hours more than half the time taking the drugs, or a patient who no longer used triptans because of adverse effects or lack of efficacy. Patients who had used triptans in the past and had complete pain relief within 2 hours more than half the time were deemed triptan-effective patients.

The analysis also looked at two other endpoints in addition to complete pain freedom: complete relief of the most-bothersome symptom of the migraine headache (photophobia for most patients), which resolved in 39% and 36% of the triptan-effective and triptan-ineffective patients, respectively, compared with placebo response rates of 27% and 23%; both between-group differences were statistically significant. A third measure of efficacy was some degree of pain relief after 2 hours, which occurred in 62% of patients in whom triptans were effective and 55% in those in whom triptans were ineffective, which were again statistically significant higher rates than among patients who received placebo.

Safety findings from the two ubrogepant pivotal trials showed good drug tolerability, with no treatment-related serious adverse events, and a profile of modest numbers of treatment-related and total adverse events similar to what occurred among patients who received placebo.

ACHIEVE I and II were funded by Allergan, the company developing ubrogepant. Dr. Hutchinson has been an adviser to and a speaker on behalf of Allergan and several other companies.

[email protected]

SOURCE: Blumenfeld AM. Headache. 2019 June;59[S1]:1-208, Abstract IOR02.

PHILADELPHIA – The oral, small molecule, calcitonin gene-related peptide receptor antagonist ubrogepant, currently under regulatory review for approval as a treatment for acute migraine headache, was as effective for migraine relief in patients with a history of triptan ineffectiveness as it was in patients for whom triptans had been effective, based on a post hoc analysis of data collected from 1,798 patients enrolled in two phase 3 trials.

Mitchel L. Zoler/MDedge News

In the roughly one-quarter of all patients who had a clinical history consistent with triptan ineffectiveness, one 50-mg dose of ubrogepant led to pain freedom 2 hours after treatment in 16% of patients, compared with a response rate of 8% in placebo-treated patients. Ubrogepant’s effectiveness rate that was about the same as seen in patients with a history of triptan effectiveness, who were about 37% of the study population, Susan Hutchinson, MD, said at the annual meeting of the American Headache Society.

Among those with a history of triptan effectiveness, 20% were pain free after 2 hours, compared with 11% of placebo-treated controls, said Dr. Hutchinson, a family physician and headache specialist who practices in Irvine, Calif. Both of these between-group differences were statistically significant. The remaining patients included in the analysis had no triptan history, and among these patients a single, 50-mg dose of ubrogepant produced pain freedom at 2 hours in 24% of patients, versus an 18% response in placebo-treated controls, a difference that fell short of statistical significance.

The analysis Dr. Hutchinson reported came from data collected in two pivotal trials of ubrogepant for treatment of an acute migraine headache, the ACHIEVE I and ACHIEVE II trials, which together randomized more than 2,600 migraine patients eligible for the study’s modified intention-to-treat analysis, and 1,798 patients from that analysis who received a 50-mg dose of ubrogepant or placebo. In March 2019, the company developing ubrogepant, Allergan, announced that the Food and Drug Administration had accepted the company’s application for marketing approval of ubrogepant as a treatment for acute migraine largely based on data from ACHIEVE I and ACHIEVE II.

The researchers defined a history of triptan ineffectiveness as a patient who never used a triptan because of a warning, precaution, or contraindication, a patient who recently used triptans but did not achieve pain freedom within 2 hours more than half the time taking the drugs, or a patient who no longer used triptans because of adverse effects or lack of efficacy. Patients who had used triptans in the past and had complete pain relief within 2 hours more than half the time were deemed triptan-effective patients.

The analysis also looked at two other endpoints in addition to complete pain freedom: complete relief of the most-bothersome symptom of the migraine headache (photophobia for most patients), which resolved in 39% and 36% of the triptan-effective and triptan-ineffective patients, respectively, compared with placebo response rates of 27% and 23%; both between-group differences were statistically significant. A third measure of efficacy was some degree of pain relief after 2 hours, which occurred in 62% of patients in whom triptans were effective and 55% in those in whom triptans were ineffective, which were again statistically significant higher rates than among patients who received placebo.

Safety findings from the two ubrogepant pivotal trials showed good drug tolerability, with no treatment-related serious adverse events, and a profile of modest numbers of treatment-related and total adverse events similar to what occurred among patients who received placebo.

ACHIEVE I and II were funded by Allergan, the company developing ubrogepant. Dr. Hutchinson has been an adviser to and a speaker on behalf of Allergan and several other companies.

[email protected]

SOURCE: Blumenfeld AM. Headache. 2019 June;59[S1]:1-208, Abstract IOR02.

PHILADELPHIA – The oral, small molecule, calcitonin gene-related peptide receptor antagonist ubrogepant, currently under regulatory review for approval as a treatment for acute migraine headache, was as effective for migraine relief in patients with a history of triptan ineffectiveness as it was in patients for whom triptans had been effective, based on a post hoc analysis of data collected from 1,798 patients enrolled in two phase 3 trials.

Mitchel L. Zoler/MDedge News

In the roughly one-quarter of all patients who had a clinical history consistent with triptan ineffectiveness, one 50-mg dose of ubrogepant led to pain freedom 2 hours after treatment in 16% of patients, compared with a response rate of 8% in placebo-treated patients. Ubrogepant’s effectiveness rate that was about the same as seen in patients with a history of triptan effectiveness, who were about 37% of the study population, Susan Hutchinson, MD, said at the annual meeting of the American Headache Society.

Among those with a history of triptan effectiveness, 20% were pain free after 2 hours, compared with 11% of placebo-treated controls, said Dr. Hutchinson, a family physician and headache specialist who practices in Irvine, Calif. Both of these between-group differences were statistically significant. The remaining patients included in the analysis had no triptan history, and among these patients a single, 50-mg dose of ubrogepant produced pain freedom at 2 hours in 24% of patients, versus an 18% response in placebo-treated controls, a difference that fell short of statistical significance.

The analysis Dr. Hutchinson reported came from data collected in two pivotal trials of ubrogepant for treatment of an acute migraine headache, the ACHIEVE I and ACHIEVE II trials, which together randomized more than 2,600 migraine patients eligible for the study’s modified intention-to-treat analysis, and 1,798 patients from that analysis who received a 50-mg dose of ubrogepant or placebo. In March 2019, the company developing ubrogepant, Allergan, announced that the Food and Drug Administration had accepted the company’s application for marketing approval of ubrogepant as a treatment for acute migraine largely based on data from ACHIEVE I and ACHIEVE II.

The researchers defined a history of triptan ineffectiveness as a patient who never used a triptan because of a warning, precaution, or contraindication, a patient who recently used triptans but did not achieve pain freedom within 2 hours more than half the time taking the drugs, or a patient who no longer used triptans because of adverse effects or lack of efficacy. Patients who had used triptans in the past and had complete pain relief within 2 hours more than half the time were deemed triptan-effective patients.

The analysis also looked at two other endpoints in addition to complete pain freedom: complete relief of the most-bothersome symptom of the migraine headache (photophobia for most patients), which resolved in 39% and 36% of the triptan-effective and triptan-ineffective patients, respectively, compared with placebo response rates of 27% and 23%; both between-group differences were statistically significant. A third measure of efficacy was some degree of pain relief after 2 hours, which occurred in 62% of patients in whom triptans were effective and 55% in those in whom triptans were ineffective, which were again statistically significant higher rates than among patients who received placebo.

Safety findings from the two ubrogepant pivotal trials showed good drug tolerability, with no treatment-related serious adverse events, and a profile of modest numbers of treatment-related and total adverse events similar to what occurred among patients who received placebo.

ACHIEVE I and II were funded by Allergan, the company developing ubrogepant. Dr. Hutchinson has been an adviser to and a speaker on behalf of Allergan and several other companies.

[email protected]

SOURCE: Blumenfeld AM. Headache. 2019 June;59[S1]:1-208, Abstract IOR02.

PHILADELPHIA – U.S. children and teens who were hospitalized because of asthma had twice the rate of migraine headache when compared with a similar pediatric population without asthma. The finding is based on an analysis of more than 11 million U.S. pediatric hospitalizations over the course of a decade.

Among children and adolescents aged 3-21 years who were hospitalized for asthma, migraine rates were significantly higher among girls, adolescents, and whites, compared with boys, children aged 12 years or younger, and nonwhites, respectively, in a trio of adjusted analyses, Riddhiben S. Patel, MD, and associates reported in a poster at the annual meeting of the American Headache Society.

“Our hope is that, by establishing an association between childhood asthma and migraine, [these children] may be more easily screened for, diagnosed, and treated early by providers,” wrote Dr. Patel, a pediatric neurologist and headache specialist at the University of Mississippi, Jackson, and associates.

Their analysis used administrative billing data collected by the Kids’ Inpatient Database, maintained by the U.S. Healthcare Cost and Utilization Project. The project includes a representative national sample of about 3 million pediatric hospital discharges every 3 years. The study used data from 11,483,103 hospitalizations of children and adolescents aged 3-21 years during 2003, 2006, 2009, and 2012, and found an overall hospitalization rate of 0.8% billed for migraine. For patients also hospitalized with a billing code for asthma, the rate jumped to 1.36%, a 120% statistically significant relative increase in migraine hospitalizations after adjustment for baseline demographic differences, the researchers said.

Among the children and adolescents hospitalized with an asthma billing code, the relative rate of also having a billing code for migraine after adjustment was a statistically significant 80% higher in girls, compared with boys, a statistically significant 7% higher in adolescents, compared with children 12 years or younger, and was significantly reduced by a relative 45% rate in nonwhites, compared with whites.

The mechanisms behind these associations are not known, but could involve mast-cell degranulation, autonomic dysfunction, or shared genetic or environmental etiologic factors, the authors said.

Dr. Patel reported no relevant disclosures.

[email protected]

SOURCE: Patel RS et al. Headache. 2019 June;59[S1]:1-208, Abstract P78.

PHILADELPHIA – U.S. children and teens who were hospitalized because of asthma had twice the rate of migraine headache when compared with a similar pediatric population without asthma. The finding is based on an analysis of more than 11 million U.S. pediatric hospitalizations over the course of a decade.

Among children and adolescents aged 3-21 years who were hospitalized for asthma, migraine rates were significantly higher among girls, adolescents, and whites, compared with boys, children aged 12 years or younger, and nonwhites, respectively, in a trio of adjusted analyses, Riddhiben S. Patel, MD, and associates reported in a poster at the annual meeting of the American Headache Society.

“Our hope is that, by establishing an association between childhood asthma and migraine, [these children] may be more easily screened for, diagnosed, and treated early by providers,” wrote Dr. Patel, a pediatric neurologist and headache specialist at the University of Mississippi, Jackson, and associates.

Their analysis used administrative billing data collected by the Kids’ Inpatient Database, maintained by the U.S. Healthcare Cost and Utilization Project. The project includes a representative national sample of about 3 million pediatric hospital discharges every 3 years. The study used data from 11,483,103 hospitalizations of children and adolescents aged 3-21 years during 2003, 2006, 2009, and 2012, and found an overall hospitalization rate of 0.8% billed for migraine. For patients also hospitalized with a billing code for asthma, the rate jumped to 1.36%, a 120% statistically significant relative increase in migraine hospitalizations after adjustment for baseline demographic differences, the researchers said.

Among the children and adolescents hospitalized with an asthma billing code, the relative rate of also having a billing code for migraine after adjustment was a statistically significant 80% higher in girls, compared with boys, a statistically significant 7% higher in adolescents, compared with children 12 years or younger, and was significantly reduced by a relative 45% rate in nonwhites, compared with whites.

The mechanisms behind these associations are not known, but could involve mast-cell degranulation, autonomic dysfunction, or shared genetic or environmental etiologic factors, the authors said.

Dr. Patel reported no relevant disclosures.

[email protected]

SOURCE: Patel RS et al. Headache. 2019 June;59[S1]:1-208, Abstract P78.

PHILADELPHIA – U.S. children and teens who were hospitalized because of asthma had twice the rate of migraine headache when compared with a similar pediatric population without asthma. The finding is based on an analysis of more than 11 million U.S. pediatric hospitalizations over the course of a decade.

Among children and adolescents aged 3-21 years who were hospitalized for asthma, migraine rates were significantly higher among girls, adolescents, and whites, compared with boys, children aged 12 years or younger, and nonwhites, respectively, in a trio of adjusted analyses, Riddhiben S. Patel, MD, and associates reported in a poster at the annual meeting of the American Headache Society.

“Our hope is that, by establishing an association between childhood asthma and migraine, [these children] may be more easily screened for, diagnosed, and treated early by providers,” wrote Dr. Patel, a pediatric neurologist and headache specialist at the University of Mississippi, Jackson, and associates.

Their analysis used administrative billing data collected by the Kids’ Inpatient Database, maintained by the U.S. Healthcare Cost and Utilization Project. The project includes a representative national sample of about 3 million pediatric hospital discharges every 3 years. The study used data from 11,483,103 hospitalizations of children and adolescents aged 3-21 years during 2003, 2006, 2009, and 2012, and found an overall hospitalization rate of 0.8% billed for migraine. For patients also hospitalized with a billing code for asthma, the rate jumped to 1.36%, a 120% statistically significant relative increase in migraine hospitalizations after adjustment for baseline demographic differences, the researchers said.

Among the children and adolescents hospitalized with an asthma billing code, the relative rate of also having a billing code for migraine after adjustment was a statistically significant 80% higher in girls, compared with boys, a statistically significant 7% higher in adolescents, compared with children 12 years or younger, and was significantly reduced by a relative 45% rate in nonwhites, compared with whites.

The mechanisms behind these associations are not known, but could involve mast-cell degranulation, autonomic dysfunction, or shared genetic or environmental etiologic factors, the authors said.

Dr. Patel reported no relevant disclosures.

[email protected]

SOURCE: Patel RS et al. Headache. 2019 June;59[S1]:1-208, Abstract P78.

PHILADELPHIA – An intravenous formulation of a calcitonin gene–related peptide inhibitor monoclonal antibody showed efficacy for preventing chronic migraine headaches for 3 months in a dose-ranging, phase 3 trial with 1,072 patients.

In a separate study with 669 patients, a single IV dose of the antibody, eptinezumab, also significantly reduced the incidence of episodic migraine headaches during 3 months of follow-up, compared with placebo. And in both the chronic and episodic migraine studies a similar 3-month effect resulted from a second IV dose of the humanized antibody that binds the calcitonin gene–related peptide (CGRP) ligand, thereby blocking the pathway, Laszlo L. Mechtler, MD, and his associates reported in a poster at the annual meeting of the American Headache Society.

Eptinezumab follows the therapeutic approach already used by three Food and Drug Administration–approved monoclonal antibody drugs that cut migraine headache recurrences by blocking the CGRP pathway by binding either the peptide ligand or its receptor: erenumab-aooe (Aimovig), fremanezumab-vfrm (Ajovy), and galcanezumab-gnlm (Emgality). Eptinezumab differs from the three approved CGRP antibodies by using an IV route of administration – the other three are delivered by subcutaneous injection – and by a 3-month dosing interval. Both erenumab-aooe and galcanezumab-gnlm are labeled for monthly administration only, while fremanezumab-vfrm is labeled for both monthly and once every 3 months dosing schedules.

The PROMISE-1 (A Multicenter Assessment of ALD403 in Frequent Episodic Migraine) trial randomized 669 patients with episodic migraine (defined as 4-14 headache days/month with at least 4 classifiable as migraine headache days) at 87 centers mostly in the United States and with some in Georgia. The PROMISE-2 (Evaluation of ALD403 (Eptinezumab) in the Prevention of Chronic Migraine) trial randomized 1,072 patients with chronic migraine (defined as a history of 15-26 headache days/month and with at least 8 of the days involving a migraine headache) at any of 145 study sites, many in the United States, in several countries.

In PROMISE-1, patients could receive as many as four serial infusions every 3 months, and up to two serial infusions in PROMISE-2, but the primary endpoint in both studies was the change in monthly migraine count from baseline during the 3 months following the first dosage.

Among patients with chronic migraine in PROMISE-2, the average monthly migraine number fell by 8.2 migraine days/month, compared with an average 5.6 monthly migraine days drop from baseline among placebo patients, which was a statistically significant difference for the higher dosage of eptinezumab tested, 300 mg. A 100-mg dose linked with an average 7.7 migraine days/month reduction, also a statistically significant difference from the placebo patients, reported Dr. Mechtler, professor of neurology at the State University of New York at Buffalo and medical director of the Dent Neurologic Institute in Buffalo, and his associates.

Among patients with episodic migraine in PROMISE-1, the 300-mg dosage cut monthly migraines by an average 4.3 migraine headache days/month, compared with 3.2 in the placebo group, a statistically significant difference. Among patients who received the 100-mg dosage, the average cut was 3.9 migraine headache days/month, also a statistically significant difference from the placebo controls.

The researchers included no safety findings in their report, but in an interview Dr. Mechtler said that eptinezumab showed an excellent safety profile that was consistent with what’s been previously reported for the approved agents from this class. He cited the safety of the drugs in the class as a major feature of their clinical utility.

PROMISE-1 and PROMISE-2 were sponsored by Alder BioPharmaceuticals, the company developing eptinezumab. Dr. Mechtler has been a speaker on behalf of Allergan, Amgen/Novartis, Boston Biomedical, Promius, Avanir, and Teva, and he has received research funding from Allergan, Autonomic Technologies, Boston Biomedical, and Teva.

[email protected]

SOURCE: Mechtler LL et al. Headache. 2019 June;59[S1]:34, Abstract P12

PHILADELPHIA – An intravenous formulation of a calcitonin gene–related peptide inhibitor monoclonal antibody showed efficacy for preventing chronic migraine headaches for 3 months in a dose-ranging, phase 3 trial with 1,072 patients.

In a separate study with 669 patients, a single IV dose of the antibody, eptinezumab, also significantly reduced the incidence of episodic migraine headaches during 3 months of follow-up, compared with placebo. And in both the chronic and episodic migraine studies a similar 3-month effect resulted from a second IV dose of the humanized antibody that binds the calcitonin gene–related peptide (CGRP) ligand, thereby blocking the pathway, Laszlo L. Mechtler, MD, and his associates reported in a poster at the annual meeting of the American Headache Society.

Eptinezumab follows the therapeutic approach already used by three Food and Drug Administration–approved monoclonal antibody drugs that cut migraine headache recurrences by blocking the CGRP pathway by binding either the peptide ligand or its receptor: erenumab-aooe (Aimovig), fremanezumab-vfrm (Ajovy), and galcanezumab-gnlm (Emgality). Eptinezumab differs from the three approved CGRP antibodies by using an IV route of administration – the other three are delivered by subcutaneous injection – and by a 3-month dosing interval. Both erenumab-aooe and galcanezumab-gnlm are labeled for monthly administration only, while fremanezumab-vfrm is labeled for both monthly and once every 3 months dosing schedules.

The PROMISE-1 (A Multicenter Assessment of ALD403 in Frequent Episodic Migraine) trial randomized 669 patients with episodic migraine (defined as 4-14 headache days/month with at least 4 classifiable as migraine headache days) at 87 centers mostly in the United States and with some in Georgia. The PROMISE-2 (Evaluation of ALD403 (Eptinezumab) in the Prevention of Chronic Migraine) trial randomized 1,072 patients with chronic migraine (defined as a history of 15-26 headache days/month and with at least 8 of the days involving a migraine headache) at any of 145 study sites, many in the United States, in several countries.

In PROMISE-1, patients could receive as many as four serial infusions every 3 months, and up to two serial infusions in PROMISE-2, but the primary endpoint in both studies was the change in monthly migraine count from baseline during the 3 months following the first dosage.

Among patients with chronic migraine in PROMISE-2, the average monthly migraine number fell by 8.2 migraine days/month, compared with an average 5.6 monthly migraine days drop from baseline among placebo patients, which was a statistically significant difference for the higher dosage of eptinezumab tested, 300 mg. A 100-mg dose linked with an average 7.7 migraine days/month reduction, also a statistically significant difference from the placebo patients, reported Dr. Mechtler, professor of neurology at the State University of New York at Buffalo and medical director of the Dent Neurologic Institute in Buffalo, and his associates.

Among patients with episodic migraine in PROMISE-1, the 300-mg dosage cut monthly migraines by an average 4.3 migraine headache days/month, compared with 3.2 in the placebo group, a statistically significant difference. Among patients who received the 100-mg dosage, the average cut was 3.9 migraine headache days/month, also a statistically significant difference from the placebo controls.

The researchers included no safety findings in their report, but in an interview Dr. Mechtler said that eptinezumab showed an excellent safety profile that was consistent with what’s been previously reported for the approved agents from this class. He cited the safety of the drugs in the class as a major feature of their clinical utility.

PROMISE-1 and PROMISE-2 were sponsored by Alder BioPharmaceuticals, the company developing eptinezumab. Dr. Mechtler has been a speaker on behalf of Allergan, Amgen/Novartis, Boston Biomedical, Promius, Avanir, and Teva, and he has received research funding from Allergan, Autonomic Technologies, Boston Biomedical, and Teva.

[email protected]

SOURCE: Mechtler LL et al. Headache. 2019 June;59[S1]:34, Abstract P12

PHILADELPHIA – An intravenous formulation of a calcitonin gene–related peptide inhibitor monoclonal antibody showed efficacy for preventing chronic migraine headaches for 3 months in a dose-ranging, phase 3 trial with 1,072 patients.

In a separate study with 669 patients, a single IV dose of the antibody, eptinezumab, also significantly reduced the incidence of episodic migraine headaches during 3 months of follow-up, compared with placebo. And in both the chronic and episodic migraine studies a similar 3-month effect resulted from a second IV dose of the humanized antibody that binds the calcitonin gene–related peptide (CGRP) ligand, thereby blocking the pathway, Laszlo L. Mechtler, MD, and his associates reported in a poster at the annual meeting of the American Headache Society.

Eptinezumab follows the therapeutic approach already used by three Food and Drug Administration–approved monoclonal antibody drugs that cut migraine headache recurrences by blocking the CGRP pathway by binding either the peptide ligand or its receptor: erenumab-aooe (Aimovig), fremanezumab-vfrm (Ajovy), and galcanezumab-gnlm (Emgality). Eptinezumab differs from the three approved CGRP antibodies by using an IV route of administration – the other three are delivered by subcutaneous injection – and by a 3-month dosing interval. Both erenumab-aooe and galcanezumab-gnlm are labeled for monthly administration only, while fremanezumab-vfrm is labeled for both monthly and once every 3 months dosing schedules.

The PROMISE-1 (A Multicenter Assessment of ALD403 in Frequent Episodic Migraine) trial randomized 669 patients with episodic migraine (defined as 4-14 headache days/month with at least 4 classifiable as migraine headache days) at 87 centers mostly in the United States and with some in Georgia. The PROMISE-2 (Evaluation of ALD403 (Eptinezumab) in the Prevention of Chronic Migraine) trial randomized 1,072 patients with chronic migraine (defined as a history of 15-26 headache days/month and with at least 8 of the days involving a migraine headache) at any of 145 study sites, many in the United States, in several countries.

In PROMISE-1, patients could receive as many as four serial infusions every 3 months, and up to two serial infusions in PROMISE-2, but the primary endpoint in both studies was the change in monthly migraine count from baseline during the 3 months following the first dosage.

Among patients with chronic migraine in PROMISE-2, the average monthly migraine number fell by 8.2 migraine days/month, compared with an average 5.6 monthly migraine days drop from baseline among placebo patients, which was a statistically significant difference for the higher dosage of eptinezumab tested, 300 mg. A 100-mg dose linked with an average 7.7 migraine days/month reduction, also a statistically significant difference from the placebo patients, reported Dr. Mechtler, professor of neurology at the State University of New York at Buffalo and medical director of the Dent Neurologic Institute in Buffalo, and his associates.

Among patients with episodic migraine in PROMISE-1, the 300-mg dosage cut monthly migraines by an average 4.3 migraine headache days/month, compared with 3.2 in the placebo group, a statistically significant difference. Among patients who received the 100-mg dosage, the average cut was 3.9 migraine headache days/month, also a statistically significant difference from the placebo controls.

The researchers included no safety findings in their report, but in an interview Dr. Mechtler said that eptinezumab showed an excellent safety profile that was consistent with what’s been previously reported for the approved agents from this class. He cited the safety of the drugs in the class as a major feature of their clinical utility.

PROMISE-1 and PROMISE-2 were sponsored by Alder BioPharmaceuticals, the company developing eptinezumab. Dr. Mechtler has been a speaker on behalf of Allergan, Amgen/Novartis, Boston Biomedical, Promius, Avanir, and Teva, and he has received research funding from Allergan, Autonomic Technologies, Boston Biomedical, and Teva.

[email protected]

SOURCE: Mechtler LL et al. Headache. 2019 June;59[S1]:34, Abstract P12

The Food and Drug Administration Arthritis Advisory Committee recommended approval of nintedanib for the treatment of interstitial lung disease in patients with systemic sclerosis by a 10-7 vote on July 25, 2019. If the FDA acts in accord with the panel’s recommendation, it would make nintedanib (Ofev) the first drug to receive marketing approval for this indication.

Nintedanib has had FDA approval for treating idiopathic pulmonary fibrosis since 2014, and the manufacturer, Boehringer Ingelheim, designed the current pivotal trial with 576 patients to broaden the indication to patients with a different but similar fibrotic lung disease, interstitial lung disease (ILD), that is a common and eventually lethal complication of systemic sclerosis. The results of the pivotal study, the SENSCIS (Safety and Efficacy of Nintedanib in Systemic Sclerosis) trial, recently appeared in print and showed that patients randomized to receive 150 mg of nintedanib orally twice daily had an average 41-mL cut in the rate of loss of forced vital capacity (FVC) during 52 weeks on treatment, compared with those randomized to placebo. This was a 44% relative reduction in rate of FVC loss that was statistically significant for the study’s primary endpoint (N Engl J Med. 2019 June 27;380[26]:2518-28).

Votes in favor of FDA approval for many on the panel seemed to stem from a combination of the fact that nintedanib met the pivotal trial’s primary endpoint; which had been developed in consultation with the FDA, as well as the absence of any new safety signals when compared with prior experience using the drug; the lack of any treatment specifically recognized as beneficial to systemic sclerosis patients who develop the terminal complication of ILD; and the challenge of running a second trial in an orphan disease with an estimated U.S. prevalence of no more than 100,000 patients. Several committee members who voted in favor of nintedanib’s approval also voiced concern that the case in favor of its benefit/risk balance was not open and shut.

“I have a fair amount of apprehension,” admitted the committee’s chair, Daniel H. Solomon, MD, a rheumatologist and professor of medicine at Harvard Medical School, Boston. “I support the needs of patients, but we don’t want to give them false hope. We need to be able to say who will benefit, and the single study [SENSCIS] results don’t tell us how to use the drug. I want to understand which patient subgroups benefit.” He suggested that the FDA mandate further data collection through postmarketing studies.

Comments from panel members who voted against recommending approval generally focused on what was generally agreed to be a very modest treatment effect with a 41-mL average difference in FVC decline that has marginal clinical meaningfulness. Although the SENSCIS results met the study’s primary endpoint it was neutral for all prespecified secondary endpoints, including a measure of quality of life, although many on the panel agreed that a good measure of quality of life in the target patient population is lacking. Some sensitivity analyses run by FDA staffers also failed to confirm the primary result. Fewer questions arose about safety, although some panelists expressed concern about gastrointestinal effects, especially diarrhea, that seemed to link with treatment, as well as a signal for an increased incidence of pneumonia among patients on nintedanib. The data also showed a possible signal of reduced efficacy among patients who also received treatment with the immunosuppressive agent mycophenolate mofetil, often used off label to treat systemic sclerosis patients with ILD. However, a statistician involved in the discussion warned against overinterpreting this or other subgroup analyses.

Dr. Solomon has received research support from AbbVie, Amgen, Bristol-Myers Squibb, Genentech, Janssen, and Pfizer.

[email protected]

The Food and Drug Administration Arthritis Advisory Committee recommended approval of nintedanib for the treatment of interstitial lung disease in patients with systemic sclerosis by a 10-7 vote on July 25, 2019. If the FDA acts in accord with the panel’s recommendation, it would make nintedanib (Ofev) the first drug to receive marketing approval for this indication.

Nintedanib has had FDA approval for treating idiopathic pulmonary fibrosis since 2014, and the manufacturer, Boehringer Ingelheim, designed the current pivotal trial with 576 patients to broaden the indication to patients with a different but similar fibrotic lung disease, interstitial lung disease (ILD), that is a common and eventually lethal complication of systemic sclerosis. The results of the pivotal study, the SENSCIS (Safety and Efficacy of Nintedanib in Systemic Sclerosis) trial, recently appeared in print and showed that patients randomized to receive 150 mg of nintedanib orally twice daily had an average 41-mL cut in the rate of loss of forced vital capacity (FVC) during 52 weeks on treatment, compared with those randomized to placebo. This was a 44% relative reduction in rate of FVC loss that was statistically significant for the study’s primary endpoint (N Engl J Med. 2019 June 27;380[26]:2518-28).

Votes in favor of FDA approval for many on the panel seemed to stem from a combination of the fact that nintedanib met the pivotal trial’s primary endpoint; which had been developed in consultation with the FDA, as well as the absence of any new safety signals when compared with prior experience using the drug; the lack of any treatment specifically recognized as beneficial to systemic sclerosis patients who develop the terminal complication of ILD; and the challenge of running a second trial in an orphan disease with an estimated U.S. prevalence of no more than 100,000 patients. Several committee members who voted in favor of nintedanib’s approval also voiced concern that the case in favor of its benefit/risk balance was not open and shut.

“I have a fair amount of apprehension,” admitted the committee’s chair, Daniel H. Solomon, MD, a rheumatologist and professor of medicine at Harvard Medical School, Boston. “I support the needs of patients, but we don’t want to give them false hope. We need to be able to say who will benefit, and the single study [SENSCIS] results don’t tell us how to use the drug. I want to understand which patient subgroups benefit.” He suggested that the FDA mandate further data collection through postmarketing studies.

Comments from panel members who voted against recommending approval generally focused on what was generally agreed to be a very modest treatment effect with a 41-mL average difference in FVC decline that has marginal clinical meaningfulness. Although the SENSCIS results met the study’s primary endpoint it was neutral for all prespecified secondary endpoints, including a measure of quality of life, although many on the panel agreed that a good measure of quality of life in the target patient population is lacking. Some sensitivity analyses run by FDA staffers also failed to confirm the primary result. Fewer questions arose about safety, although some panelists expressed concern about gastrointestinal effects, especially diarrhea, that seemed to link with treatment, as well as a signal for an increased incidence of pneumonia among patients on nintedanib. The data also showed a possible signal of reduced efficacy among patients who also received treatment with the immunosuppressive agent mycophenolate mofetil, often used off label to treat systemic sclerosis patients with ILD. However, a statistician involved in the discussion warned against overinterpreting this or other subgroup analyses.

Dr. Solomon has received research support from AbbVie, Amgen, Bristol-Myers Squibb, Genentech, Janssen, and Pfizer.

[email protected]

The Food and Drug Administration Arthritis Advisory Committee recommended approval of nintedanib for the treatment of interstitial lung disease in patients with systemic sclerosis by a 10-7 vote on July 25, 2019. If the FDA acts in accord with the panel’s recommendation, it would make nintedanib (Ofev) the first drug to receive marketing approval for this indication.

Nintedanib has had FDA approval for treating idiopathic pulmonary fibrosis since 2014, and the manufacturer, Boehringer Ingelheim, designed the current pivotal trial with 576 patients to broaden the indication to patients with a different but similar fibrotic lung disease, interstitial lung disease (ILD), that is a common and eventually lethal complication of systemic sclerosis. The results of the pivotal study, the SENSCIS (Safety and Efficacy of Nintedanib in Systemic Sclerosis) trial, recently appeared in print and showed that patients randomized to receive 150 mg of nintedanib orally twice daily had an average 41-mL cut in the rate of loss of forced vital capacity (FVC) during 52 weeks on treatment, compared with those randomized to placebo. This was a 44% relative reduction in rate of FVC loss that was statistically significant for the study’s primary endpoint (N Engl J Med. 2019 June 27;380[26]:2518-28).

Votes in favor of FDA approval for many on the panel seemed to stem from a combination of the fact that nintedanib met the pivotal trial’s primary endpoint; which had been developed in consultation with the FDA, as well as the absence of any new safety signals when compared with prior experience using the drug; the lack of any treatment specifically recognized as beneficial to systemic sclerosis patients who develop the terminal complication of ILD; and the challenge of running a second trial in an orphan disease with an estimated U.S. prevalence of no more than 100,000 patients. Several committee members who voted in favor of nintedanib’s approval also voiced concern that the case in favor of its benefit/risk balance was not open and shut.

“I have a fair amount of apprehension,” admitted the committee’s chair, Daniel H. Solomon, MD, a rheumatologist and professor of medicine at Harvard Medical School, Boston. “I support the needs of patients, but we don’t want to give them false hope. We need to be able to say who will benefit, and the single study [SENSCIS] results don’t tell us how to use the drug. I want to understand which patient subgroups benefit.” He suggested that the FDA mandate further data collection through postmarketing studies.

Comments from panel members who voted against recommending approval generally focused on what was generally agreed to be a very modest treatment effect with a 41-mL average difference in FVC decline that has marginal clinical meaningfulness. Although the SENSCIS results met the study’s primary endpoint it was neutral for all prespecified secondary endpoints, including a measure of quality of life, although many on the panel agreed that a good measure of quality of life in the target patient population is lacking. Some sensitivity analyses run by FDA staffers also failed to confirm the primary result. Fewer questions arose about safety, although some panelists expressed concern about gastrointestinal effects, especially diarrhea, that seemed to link with treatment, as well as a signal for an increased incidence of pneumonia among patients on nintedanib. The data also showed a possible signal of reduced efficacy among patients who also received treatment with the immunosuppressive agent mycophenolate mofetil, often used off label to treat systemic sclerosis patients with ILD. However, a statistician involved in the discussion warned against overinterpreting this or other subgroup analyses.

Dr. Solomon has received research support from AbbVie, Amgen, Bristol-Myers Squibb, Genentech, Janssen, and Pfizer.

[email protected]

PHILADELPHIA – Atogepant, an oral small-molecule migraine drug from the “gepant” class, showed safety and efficacy for preventing migraine headaches in a phase 2/3, dose-ranging trial with 825 evaluable patients.

Mitchel L. Zoler/MDedge News

Atogepant is the first drug from this novel class to undergo efficacy testing in an advanced-phase trial for prevention of migraine headaches, David W. Dodick, MD, said at the annual meeting of the American Headache Society. Two other agents from the gepant class, rimegepant and ubrogepant, have undergone phase 3 testing for acute treatment of migraine headache, and both drugs are now under Food and Drug Administration consideration for an acute-treatment indication.

Three monoclonal antibodies to the calcitonin gene–related peptide (CGRP) receptor have received FDA marketing approval since 2018 for migraine headache prevention. The small-molecule antagonists to the CGRP receptor in the gepant class have an effect similar to the monoclonal antibodies, but with different dosage schedules, an oral route of administration, and with half-lives measured in hours, compared with days and weeks.

“Historically the [gepant] class of drugs was designed for acute treatment, and a couple of drugs from this class didn’t make it because of liver toxicity, but the liver toxicity is not a class effect.” The more recent candidate agents – atogepant, ubrogepant, and rimegepant – have shown hepatic safety as well as overall safety, noted Dr. Dodick, a neurologist and headache specialist at the Mayo Clinic in Phoenix.

If these gepant agents eventually receive FDA approval, which seems likely based on the evidence collected so far, they would collectively form “the only class to have both acute and preventive indications” for migraine, Dr. Dodick said in an interview. The preventive efficacy seen with atogepant in the current study is likely a class effect that has not yet been tested in ubrogepant and rimegepant.

In the multicenter study he reported, 834 patients, 86% of them women, were randomized to placebo or to any of five dosages of atogepant, ranging from 10 mg once daily to 60 mg b.i.d. Study participants had a history of episodic migraine with an average of nearly eight migraine-headache days per month and an average disease duration of about 19 years. The patients’ average age was about 40 years, and 72% had never before used a migraine-preventive treatment. Half had migraine without aura, about a quarter had migraine with aura, and a quarter had migraines of both types.


The researchers had safety data for 825 patients, and efficacy data for 795.

The study’s primary efficacy endpoint was the reduction from baseline in average migraine headache days per month after 12 weeks on treatment. Average migraine headache days fell by 2.85 days in the placebo group and by 3.55-4.23 days in the atogepant treatment groups, a significant difference. The reduction depended on the dosage patients received, but there was no clear dose-response relationship.

At least a 50% drop in average monthly headache day totals was seen in 40% of the placebo patients and in 52%-62% of the patients on atogepant, depending on their dosage. In this case, a signal appeared for a dose-response relationship as only the two subgroups with the patients who received the largest atogepant dosages showed statistically significant improvements in response, compared with placebo.

All patients on atogepant, regardless of their dosage, also had statistically significant reductions in their use of acute migraine medications, compared with placebo patients.

The level of benefit beyond placebo seen in these results was “clinically meaningful,” and roughly comparable with the preventive benefit seen with both the CGRP receptor antagonist monoclonal antibodies, as well as with the three conventional agents most commonly used for migraine headache prevention in current U.S. practice: topiramate, amitriptyline, and propranolol, Dr. Dodick said. Amitriptyline is not approved for this indication.

The adverse event profile among patients who received atogepant was about the same as it was among the placebo recipients. Seven study patients had serious treatment-related adverse effects; two of these patients were in the placebo arm of 186 patients. The most common adverse events were nausea, constipation, and fatigue, and were seen mostly at the highest dosage of atogepant. The incidence of elevated liver enzymes was low and similar in the placebo and drug-treated patients. Two patients, one on placebo and one on atogepant, had their liver enzymes reach at least five times the upper limit of normal. None had their enzymes reach at least 10 times the upper limit of normal, and no patients in the study had a response that fulfilled “Hy’s law,” which flags drug-induced liver injury as patients who develop the combination of elevated liver enzymes, elevated bilirubin, and depressed alkaline phosphatase.

The study was sponsored by Allergan, the company developing atogepant and ubrogepant. Dr. Dodick has been a consultant to Allergan and to several other drug companies.

[email protected]

PHILADELPHIA – Atogepant, an oral small-molecule migraine drug from the “gepant” class, showed safety and efficacy for preventing migraine headaches in a phase 2/3, dose-ranging trial with 825 evaluable patients.

Mitchel L. Zoler/MDedge News

Atogepant is the first drug from this novel class to undergo efficacy testing in an advanced-phase trial for prevention of migraine headaches, David W. Dodick, MD, said at the annual meeting of the American Headache Society. Two other agents from the gepant class, rimegepant and ubrogepant, have undergone phase 3 testing for acute treatment of migraine headache, and both drugs are now under Food and Drug Administration consideration for an acute-treatment indication.

Three monoclonal antibodies to the calcitonin gene–related peptide (CGRP) receptor have received FDA marketing approval since 2018 for migraine headache prevention. The small-molecule antagonists to the CGRP receptor in the gepant class have an effect similar to the monoclonal antibodies, but with different dosage schedules, an oral route of administration, and with half-lives measured in hours, compared with days and weeks.

“Historically the [gepant] class of drugs was designed for acute treatment, and a couple of drugs from this class didn’t make it because of liver toxicity, but the liver toxicity is not a class effect.” The more recent candidate agents – atogepant, ubrogepant, and rimegepant – have shown hepatic safety as well as overall safety, noted Dr. Dodick, a neurologist and headache specialist at the Mayo Clinic in Phoenix.

If these gepant agents eventually receive FDA approval, which seems likely based on the evidence collected so far, they would collectively form “the only class to have both acute and preventive indications” for migraine, Dr. Dodick said in an interview. The preventive efficacy seen with atogepant in the current study is likely a class effect that has not yet been tested in ubrogepant and rimegepant.

In the multicenter study he reported, 834 patients, 86% of them women, were randomized to placebo or to any of five dosages of atogepant, ranging from 10 mg once daily to 60 mg b.i.d. Study participants had a history of episodic migraine with an average of nearly eight migraine-headache days per month and an average disease duration of about 19 years. The patients’ average age was about 40 years, and 72% had never before used a migraine-preventive treatment. Half had migraine without aura, about a quarter had migraine with aura, and a quarter had migraines of both types.


The researchers had safety data for 825 patients, and efficacy data for 795.

The study’s primary efficacy endpoint was the reduction from baseline in average migraine headache days per month after 12 weeks on treatment. Average migraine headache days fell by 2.85 days in the placebo group and by 3.55-4.23 days in the atogepant treatment groups, a significant difference. The reduction depended on the dosage patients received, but there was no clear dose-response relationship.

At least a 50% drop in average monthly headache day totals was seen in 40% of the placebo patients and in 52%-62% of the patients on atogepant, depending on their dosage. In this case, a signal appeared for a dose-response relationship as only the two subgroups with the patients who received the largest atogepant dosages showed statistically significant improvements in response, compared with placebo.

All patients on atogepant, regardless of their dosage, also had statistically significant reductions in their use of acute migraine medications, compared with placebo patients.

The level of benefit beyond placebo seen in these results was “clinically meaningful,” and roughly comparable with the preventive benefit seen with both the CGRP receptor antagonist monoclonal antibodies, as well as with the three conventional agents most commonly used for migraine headache prevention in current U.S. practice: topiramate, amitriptyline, and propranolol, Dr. Dodick said. Amitriptyline is not approved for this indication.

The adverse event profile among patients who received atogepant was about the same as it was among the placebo recipients. Seven study patients had serious treatment-related adverse effects; two of these patients were in the placebo arm of 186 patients. The most common adverse events were nausea, constipation, and fatigue, and were seen mostly at the highest dosage of atogepant. The incidence of elevated liver enzymes was low and similar in the placebo and drug-treated patients. Two patients, one on placebo and one on atogepant, had their liver enzymes reach at least five times the upper limit of normal. None had their enzymes reach at least 10 times the upper limit of normal, and no patients in the study had a response that fulfilled “Hy’s law,” which flags drug-induced liver injury as patients who develop the combination of elevated liver enzymes, elevated bilirubin, and depressed alkaline phosphatase.

The study was sponsored by Allergan, the company developing atogepant and ubrogepant. Dr. Dodick has been a consultant to Allergan and to several other drug companies.

[email protected]

PHILADELPHIA – Atogepant, an oral small-molecule migraine drug from the “gepant” class, showed safety and efficacy for preventing migraine headaches in a phase 2/3, dose-ranging trial with 825 evaluable patients.

Mitchel L. Zoler/MDedge News

Atogepant is the first drug from this novel class to undergo efficacy testing in an advanced-phase trial for prevention of migraine headaches, David W. Dodick, MD, said at the annual meeting of the American Headache Society. Two other agents from the gepant class, rimegepant and ubrogepant, have undergone phase 3 testing for acute treatment of migraine headache, and both drugs are now under Food and Drug Administration consideration for an acute-treatment indication.

Three monoclonal antibodies to the calcitonin gene–related peptide (CGRP) receptor have received FDA marketing approval since 2018 for migraine headache prevention. The small-molecule antagonists to the CGRP receptor in the gepant class have an effect similar to the monoclonal antibodies, but with different dosage schedules, an oral route of administration, and with half-lives measured in hours, compared with days and weeks.

“Historically the [gepant] class of drugs was designed for acute treatment, and a couple of drugs from this class didn’t make it because of liver toxicity, but the liver toxicity is not a class effect.” The more recent candidate agents – atogepant, ubrogepant, and rimegepant – have shown hepatic safety as well as overall safety, noted Dr. Dodick, a neurologist and headache specialist at the Mayo Clinic in Phoenix.

If these gepant agents eventually receive FDA approval, which seems likely based on the evidence collected so far, they would collectively form “the only class to have both acute and preventive indications” for migraine, Dr. Dodick said in an interview. The preventive efficacy seen with atogepant in the current study is likely a class effect that has not yet been tested in ubrogepant and rimegepant.

In the multicenter study he reported, 834 patients, 86% of them women, were randomized to placebo or to any of five dosages of atogepant, ranging from 10 mg once daily to 60 mg b.i.d. Study participants had a history of episodic migraine with an average of nearly eight migraine-headache days per month and an average disease duration of about 19 years. The patients’ average age was about 40 years, and 72% had never before used a migraine-preventive treatment. Half had migraine without aura, about a quarter had migraine with aura, and a quarter had migraines of both types.


The researchers had safety data for 825 patients, and efficacy data for 795.

The study’s primary efficacy endpoint was the reduction from baseline in average migraine headache days per month after 12 weeks on treatment. Average migraine headache days fell by 2.85 days in the placebo group and by 3.55-4.23 days in the atogepant treatment groups, a significant difference. The reduction depended on the dosage patients received, but there was no clear dose-response relationship.

At least a 50% drop in average monthly headache day totals was seen in 40% of the placebo patients and in 52%-62% of the patients on atogepant, depending on their dosage. In this case, a signal appeared for a dose-response relationship as only the two subgroups with the patients who received the largest atogepant dosages showed statistically significant improvements in response, compared with placebo.

All patients on atogepant, regardless of their dosage, also had statistically significant reductions in their use of acute migraine medications, compared with placebo patients.

The level of benefit beyond placebo seen in these results was “clinically meaningful,” and roughly comparable with the preventive benefit seen with both the CGRP receptor antagonist monoclonal antibodies, as well as with the three conventional agents most commonly used for migraine headache prevention in current U.S. practice: topiramate, amitriptyline, and propranolol, Dr. Dodick said. Amitriptyline is not approved for this indication.

The adverse event profile among patients who received atogepant was about the same as it was among the placebo recipients. Seven study patients had serious treatment-related adverse effects; two of these patients were in the placebo arm of 186 patients. The most common adverse events were nausea, constipation, and fatigue, and were seen mostly at the highest dosage of atogepant. The incidence of elevated liver enzymes was low and similar in the placebo and drug-treated patients. Two patients, one on placebo and one on atogepant, had their liver enzymes reach at least five times the upper limit of normal. None had their enzymes reach at least 10 times the upper limit of normal, and no patients in the study had a response that fulfilled “Hy’s law,” which flags drug-induced liver injury as patients who develop the combination of elevated liver enzymes, elevated bilirubin, and depressed alkaline phosphatase.

The study was sponsored by Allergan, the company developing atogepant and ubrogepant. Dr. Dodick has been a consultant to Allergan and to several other drug companies.

[email protected]