Journal of Clinical Outcomes Management

The use of ultrasound in screening for psoriatic arthritis in patients with psoriasis could reduce the number of unnecessary referrals to rheumatologists, according to a research letter published in the British Journal of Dermatology.

Bogdanhoda/Thinkstock

Up to one-third of patients with psoriasis have underlying psoriatic arthritis (PsA), but half of all patients with psoriasis experience nonspecific musculoskeletal complaints.

“Different screening tools have been developed for the dermatology practice to distinguish patients with a higher likelihood of having PsA; however, the low specificities of these tools limit their use in clinical practice,” wrote Dilek Solmaz, MD, and colleagues at the University of Ottawa.

In this prospective study, 51 patients with psoriasis were screened for referral to a rheumatologist using the Early Arthritis for Psoriatic Patients and Psoriasis Epidemiology Screening Tool questionnaires. They also underwent a limited ultrasound scanning of wrists, hands, feet, and the most painful joint, which was reviewed by experienced rheumatologists.

A dermatologist was asked to make a decision on referral based on the questionnaire data alone, then invited to revisit that decision after viewing the ultrasound results. When basing their decision on the questionnaires only, the dermatologist decided to refer 92% of patients to a rheumatologist. Of these patients, 40% were subsequently diagnosed with PsA, which represented a sensitivity of 95% but specificity of just 9%.

After reviewing the ultrasound data, the dermatologist revised their recommendations and only referred 43% of patients. Of these, 68% were later diagnosed with psoriatic arthritis. Among the patients who were not referred after the ultrasound review, five were diagnosed with PsA, but two had isolated axial involvement with no peripheral joint disease. Excluding these two cases, the sensitivity decreased to 88% but specificity increased to 77%.

“Screening tools in psoriasis that have high sensitivities usually have low specificities, which means a higher number of patients to be referred to rheumatology than needed,” the authors wrote. “Our study demonstrated that a musculoskeletal [ultrasound] based on a predefined protocol improves the referrals made to rheumatology.”

The authors did note that the ultrasounds were reviewed by experienced rheumatologists, so the results might not be generalizable to less-experienced sonographers without experience in musculoskeletal disorders.

The study was funded by AbbVie. One author declared receiving funding for a fellowship from UCB. Two authors declared honoraria and advisory consultancies with the pharmaceutical sector, including AbbVie.

SOURCE: Solmaz D et al. Br J Dermatol. 2019 Nov 28. doi: 10.1111/bjd.18515.

The use of ultrasound in screening for psoriatic arthritis in patients with psoriasis could reduce the number of unnecessary referrals to rheumatologists, according to a research letter published in the British Journal of Dermatology.

Bogdanhoda/Thinkstock

Up to one-third of patients with psoriasis have underlying psoriatic arthritis (PsA), but half of all patients with psoriasis experience nonspecific musculoskeletal complaints.

“Different screening tools have been developed for the dermatology practice to distinguish patients with a higher likelihood of having PsA; however, the low specificities of these tools limit their use in clinical practice,” wrote Dilek Solmaz, MD, and colleagues at the University of Ottawa.

In this prospective study, 51 patients with psoriasis were screened for referral to a rheumatologist using the Early Arthritis for Psoriatic Patients and Psoriasis Epidemiology Screening Tool questionnaires. They also underwent a limited ultrasound scanning of wrists, hands, feet, and the most painful joint, which was reviewed by experienced rheumatologists.

A dermatologist was asked to make a decision on referral based on the questionnaire data alone, then invited to revisit that decision after viewing the ultrasound results. When basing their decision on the questionnaires only, the dermatologist decided to refer 92% of patients to a rheumatologist. Of these patients, 40% were subsequently diagnosed with PsA, which represented a sensitivity of 95% but specificity of just 9%.

After reviewing the ultrasound data, the dermatologist revised their recommendations and only referred 43% of patients. Of these, 68% were later diagnosed with psoriatic arthritis. Among the patients who were not referred after the ultrasound review, five were diagnosed with PsA, but two had isolated axial involvement with no peripheral joint disease. Excluding these two cases, the sensitivity decreased to 88% but specificity increased to 77%.

“Screening tools in psoriasis that have high sensitivities usually have low specificities, which means a higher number of patients to be referred to rheumatology than needed,” the authors wrote. “Our study demonstrated that a musculoskeletal [ultrasound] based on a predefined protocol improves the referrals made to rheumatology.”

The authors did note that the ultrasounds were reviewed by experienced rheumatologists, so the results might not be generalizable to less-experienced sonographers without experience in musculoskeletal disorders.

The study was funded by AbbVie. One author declared receiving funding for a fellowship from UCB. Two authors declared honoraria and advisory consultancies with the pharmaceutical sector, including AbbVie.

SOURCE: Solmaz D et al. Br J Dermatol. 2019 Nov 28. doi: 10.1111/bjd.18515.

The use of ultrasound in screening for psoriatic arthritis in patients with psoriasis could reduce the number of unnecessary referrals to rheumatologists, according to a research letter published in the British Journal of Dermatology.

Bogdanhoda/Thinkstock

Up to one-third of patients with psoriasis have underlying psoriatic arthritis (PsA), but half of all patients with psoriasis experience nonspecific musculoskeletal complaints.

“Different screening tools have been developed for the dermatology practice to distinguish patients with a higher likelihood of having PsA; however, the low specificities of these tools limit their use in clinical practice,” wrote Dilek Solmaz, MD, and colleagues at the University of Ottawa.

In this prospective study, 51 patients with psoriasis were screened for referral to a rheumatologist using the Early Arthritis for Psoriatic Patients and Psoriasis Epidemiology Screening Tool questionnaires. They also underwent a limited ultrasound scanning of wrists, hands, feet, and the most painful joint, which was reviewed by experienced rheumatologists.

A dermatologist was asked to make a decision on referral based on the questionnaire data alone, then invited to revisit that decision after viewing the ultrasound results. When basing their decision on the questionnaires only, the dermatologist decided to refer 92% of patients to a rheumatologist. Of these patients, 40% were subsequently diagnosed with PsA, which represented a sensitivity of 95% but specificity of just 9%.

After reviewing the ultrasound data, the dermatologist revised their recommendations and only referred 43% of patients. Of these, 68% were later diagnosed with psoriatic arthritis. Among the patients who were not referred after the ultrasound review, five were diagnosed with PsA, but two had isolated axial involvement with no peripheral joint disease. Excluding these two cases, the sensitivity decreased to 88% but specificity increased to 77%.

“Screening tools in psoriasis that have high sensitivities usually have low specificities, which means a higher number of patients to be referred to rheumatology than needed,” the authors wrote. “Our study demonstrated that a musculoskeletal [ultrasound] based on a predefined protocol improves the referrals made to rheumatology.”

The authors did note that the ultrasounds were reviewed by experienced rheumatologists, so the results might not be generalizable to less-experienced sonographers without experience in musculoskeletal disorders.

The study was funded by AbbVie. One author declared receiving funding for a fellowship from UCB. Two authors declared honoraria and advisory consultancies with the pharmaceutical sector, including AbbVie.

SOURCE: Solmaz D et al. Br J Dermatol. 2019 Nov 28. doi: 10.1111/bjd.18515.

BALTIMORE – Investigators from the University of California, San Francisco, are working with medical directors across the state to update county emergency medical services protocols to ensure patients in status epilepticus get 10 mg IM midazolam in the field, per national treatment guidelines from the American Epilepsy Society.

The work comes in the wake of a recent research letter in JAMA where the UCSF team reported that, across 33 emergency medical services (EMS) in California, only 2 included 10 mg midazolam IM per the guidelines, advice based on randomized, controlled clinical trials that found it to be safe and effective for stopping prehospital seizures in adults.

“Making people aware of the problem [is having] an impact,” said investigator Elan Guterman, MD, a neurology hospitalist and assistant professor of neurology at the university.

In a follow-up review at the annual meeting of the American Epilepsy Society, the team took a deep dive into the situation in Alameda County, just east of San Francisco and including the city of Oakland, as an indicator of what’s been going on across the state.

Patients had to have an EMS record of active seizures, meaning more than two within 5 minutes or a single seizure lasting more than 5 minutes. Alameda ambulance crews, like most, carry intramuscular midazolam because it’s more shelf stable than the two other first-line options, lorazepam and diazepam, and doesn’t require an intravenous line.

Among the 2,494 adults treated for status epilepticus from 2013 to 2018, just 62% received intramuscular midazolam, and only 39% got a dose of 5 mg or more. Not a single patient received the recommended 10-mg IM injection.

In short, “at the time when it’s the most important to act quickly, patients were not receiving the care they needed,” and the problem isn’t likely limited to California, Dr. Guterman said.

When patients did get 5 mg or more, they were less likely to reseize and require additional doses (adjusted odds ratio, 0.59; 95% CI, 0.4-0.86). Also – and counterintuitively given the concern about benzodiazepines and respiratory depression – the team found that higher initial doses of 5 mg or more were actually associated with a lower need for respiratory support, including intubation (OR, 0.81; 95% CI, 0.67-0.99).

It’s possible ambulance crews were erring on the side of caution. People who got midazolam were more likely to have an established diagnosis of epilepsy (68% vs. 62%; P less than .01) and less likely to have been abusing drugs or alcohol (12.5% vs. 16.3%; P less than .01).

But an abundance of caution doesn’t fully explain it; even among people known to have epilepsy, many weren’t treated with midazolam and none at the appropriate dose.

Dr. Guterman thinks the bigger issue is what was reported in the research letter: Local EMS protocols simply haven’t been updated to include current best practices. EMS services might not even be aware of them, which is why she and her colleagues have been meeting with county medical directors.

“The first step is making sure the EMS world is aware of this gap in care, and motivating them to address it,” she said.

Patients in the study were a mean of 53 years old, and just over half were men.

There was no industry funding for the study, and Dr. Guterman didn’t report any relevant disclosures.

[email protected]

SOURCE: Guterman E et al. AES 2019, Abstract 1.394.

BALTIMORE – Investigators from the University of California, San Francisco, are working with medical directors across the state to update county emergency medical services protocols to ensure patients in status epilepticus get 10 mg IM midazolam in the field, per national treatment guidelines from the American Epilepsy Society.

The work comes in the wake of a recent research letter in JAMA where the UCSF team reported that, across 33 emergency medical services (EMS) in California, only 2 included 10 mg midazolam IM per the guidelines, advice based on randomized, controlled clinical trials that found it to be safe and effective for stopping prehospital seizures in adults.

“Making people aware of the problem [is having] an impact,” said investigator Elan Guterman, MD, a neurology hospitalist and assistant professor of neurology at the university.

In a follow-up review at the annual meeting of the American Epilepsy Society, the team took a deep dive into the situation in Alameda County, just east of San Francisco and including the city of Oakland, as an indicator of what’s been going on across the state.

Patients had to have an EMS record of active seizures, meaning more than two within 5 minutes or a single seizure lasting more than 5 minutes. Alameda ambulance crews, like most, carry intramuscular midazolam because it’s more shelf stable than the two other first-line options, lorazepam and diazepam, and doesn’t require an intravenous line.

Among the 2,494 adults treated for status epilepticus from 2013 to 2018, just 62% received intramuscular midazolam, and only 39% got a dose of 5 mg or more. Not a single patient received the recommended 10-mg IM injection.

In short, “at the time when it’s the most important to act quickly, patients were not receiving the care they needed,” and the problem isn’t likely limited to California, Dr. Guterman said.

When patients did get 5 mg or more, they were less likely to reseize and require additional doses (adjusted odds ratio, 0.59; 95% CI, 0.4-0.86). Also – and counterintuitively given the concern about benzodiazepines and respiratory depression – the team found that higher initial doses of 5 mg or more were actually associated with a lower need for respiratory support, including intubation (OR, 0.81; 95% CI, 0.67-0.99).

It’s possible ambulance crews were erring on the side of caution. People who got midazolam were more likely to have an established diagnosis of epilepsy (68% vs. 62%; P less than .01) and less likely to have been abusing drugs or alcohol (12.5% vs. 16.3%; P less than .01).

But an abundance of caution doesn’t fully explain it; even among people known to have epilepsy, many weren’t treated with midazolam and none at the appropriate dose.

Dr. Guterman thinks the bigger issue is what was reported in the research letter: Local EMS protocols simply haven’t been updated to include current best practices. EMS services might not even be aware of them, which is why she and her colleagues have been meeting with county medical directors.

“The first step is making sure the EMS world is aware of this gap in care, and motivating them to address it,” she said.

Patients in the study were a mean of 53 years old, and just over half were men.

There was no industry funding for the study, and Dr. Guterman didn’t report any relevant disclosures.

[email protected]

SOURCE: Guterman E et al. AES 2019, Abstract 1.394.

BALTIMORE – Investigators from the University of California, San Francisco, are working with medical directors across the state to update county emergency medical services protocols to ensure patients in status epilepticus get 10 mg IM midazolam in the field, per national treatment guidelines from the American Epilepsy Society.

The work comes in the wake of a recent research letter in JAMA where the UCSF team reported that, across 33 emergency medical services (EMS) in California, only 2 included 10 mg midazolam IM per the guidelines, advice based on randomized, controlled clinical trials that found it to be safe and effective for stopping prehospital seizures in adults.

“Making people aware of the problem [is having] an impact,” said investigator Elan Guterman, MD, a neurology hospitalist and assistant professor of neurology at the university.

In a follow-up review at the annual meeting of the American Epilepsy Society, the team took a deep dive into the situation in Alameda County, just east of San Francisco and including the city of Oakland, as an indicator of what’s been going on across the state.

Patients had to have an EMS record of active seizures, meaning more than two within 5 minutes or a single seizure lasting more than 5 minutes. Alameda ambulance crews, like most, carry intramuscular midazolam because it’s more shelf stable than the two other first-line options, lorazepam and diazepam, and doesn’t require an intravenous line.

Among the 2,494 adults treated for status epilepticus from 2013 to 2018, just 62% received intramuscular midazolam, and only 39% got a dose of 5 mg or more. Not a single patient received the recommended 10-mg IM injection.

In short, “at the time when it’s the most important to act quickly, patients were not receiving the care they needed,” and the problem isn’t likely limited to California, Dr. Guterman said.

When patients did get 5 mg or more, they were less likely to reseize and require additional doses (adjusted odds ratio, 0.59; 95% CI, 0.4-0.86). Also – and counterintuitively given the concern about benzodiazepines and respiratory depression – the team found that higher initial doses of 5 mg or more were actually associated with a lower need for respiratory support, including intubation (OR, 0.81; 95% CI, 0.67-0.99).

It’s possible ambulance crews were erring on the side of caution. People who got midazolam were more likely to have an established diagnosis of epilepsy (68% vs. 62%; P less than .01) and less likely to have been abusing drugs or alcohol (12.5% vs. 16.3%; P less than .01).

But an abundance of caution doesn’t fully explain it; even among people known to have epilepsy, many weren’t treated with midazolam and none at the appropriate dose.

Dr. Guterman thinks the bigger issue is what was reported in the research letter: Local EMS protocols simply haven’t been updated to include current best practices. EMS services might not even be aware of them, which is why she and her colleagues have been meeting with county medical directors.

“The first step is making sure the EMS world is aware of this gap in care, and motivating them to address it,” she said.

Patients in the study were a mean of 53 years old, and just over half were men.

There was no industry funding for the study, and Dr. Guterman didn’t report any relevant disclosures.

[email protected]

SOURCE: Guterman E et al. AES 2019, Abstract 1.394.

A federal appeals court ruled Dec. 18 that the individual mandate of the Affordable Care Act (ACA) is unconstitutional, but the panel sent the case back to a lower court to decide how much of the remainder of the law could topple along with it.

The three-judge panel of the New Orleans-based U.S. Fifth Circuit Court of Appeals said, “The individual mandate is unconstitutional because, under [a previous ruling, National Federation of Independent Business v Sebelius], it finds no constitutional footing in either the Interstate Commerce Clause or the Necessary and Proper Clause.”

The ruling upholds a December 2018 US District Court decision in which Judge Reed O’Connor found that the individual mandate that most Americans must have health insurance or pay a fine was unconstitutional and that without it the ACA itself was invalid.

In sending the case back to a Texas district court, however, the federal panel is asking for a central question to be resolved: Whether the individual mandate is “severable” from the rest of the law, while the rest of the law can be left intact.

If the district court eventually decides that the individual mandate cannot be severed from the rest of the ACA, the entire law will likely be ruled invalid, and some 24 million Americans could lose health coverage.

“Today’s ruling is the result of the Trump administration and congressional Republicans attempting to make dangerous health policy using the courts since they failed to succeed in Congress,” House Ways and Means Committee Chairman Richard E. Neal (D-Mass.) said in a statement. “This is a blow to our nation’s health care system and the millions of Americans who have gained coverage and protections under the Affordable Care Act. Democrats will continue to fight to protect Americans’ access to quality, affordable care.”

Some groups are applauding the decision, though. The Citizens’ Council for Health Freedom (CCHF), which filed an amicus brief with the Fifth Circuit arguing against the ACA, said it wants more.

“We are pleased with the Fifth Circuit Court of Appeals ruling, but it didn’t go far enough,” said Twila Brase, president and cofounder of CCHF, in a statement. “The individual mandate cannot be severed from the rest of the 2,700-page Affordable Care Act, thus the court should have ruled that the entire law is invalid, as the lower district court found.

“As the Court notes in the first paragraph of the ruling, we argued in our Amicus Brief, filed jointly with the Association of American Physicians and Surgeons, that the Act ‘has deprived patients nationwide of a competitive market for affordable high-deductible health insurance,’ leaving ‘patients with no alternative to ... skyrocketing premiums,’ “ Ms. Brase added. “Sending it back to the lower court, which already ruled the right way, continues to deprive citizens and patients of the affordable coverage that freedom from Obamacare would bring.”
 

Future uncertain

The ruling in Texas v Azar is not a surprise because, during oral arguments in July, as reported by Medscape Medical News, at least two of the three judges – Jennifer Walker Elrod, appointed by President George W. Bush in 2007, and Kurt Engelhardt, appointed by President Donald J. Trump in 2018 – appeared to be more receptive to the arguments of a group of 18 Republican states and two individuals seeking to invalidate the ACA.

Judge Carolyn Dineen King, appointed by President Jimmy Carter in 1979, did not comment during the hearing.

The Trump administration chose not to defend the ACA, but it does not seem entirely prepared for what might happen if the law is overturned. In a briefing before the Fifth Circuit hearing, the administration argued that, if ultimately the law is ruled unconstitutional, it should be struck down only in the states seeking to overturn the law.

“A lot of this has to get sorted out – it’s complicated,” said August E. Flentje, a U.S. Department of Justice lawyer, at the oral arguments in July.

For now, though, the ACA remains.

“In 2012, the Supreme Court upheld Obamacare, despite serious constitutional issues with the federal government forcing Americans to purchase a product from a private company. Until an ultimate decision is made by the Supreme Court or Congress decides otherwise, the Affordable Care Act will remain the law of the land,” Senate Finance Committee Chairman Chuck Grassley (R-Iowa), said in a statement.

And those who have led the court battle to keep the ACA intact plan to keep fighting. “For now, the President got the gift he wanted – uncertainty in the health care system and a pathway to repeal – so that the health care that seniors, workers, and families secured under the Affordable Care Act can be yanked from under them. This decision could take us to a dangerous and irresponsible place, not just for the 133 million Americans with pre-existing conditions, but for our seniors who use Medicare, our children under the age of 26, and the 20 million additional Americans covered directly through the ACA marketplace. California will move swiftly to challenge this decision because this could mean the difference between life and death for so many Americans and their families,” California Attorney General Xavier Becerra said in a statement.

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

A federal appeals court ruled Dec. 18 that the individual mandate of the Affordable Care Act (ACA) is unconstitutional, but the panel sent the case back to a lower court to decide how much of the remainder of the law could topple along with it.

The three-judge panel of the New Orleans-based U.S. Fifth Circuit Court of Appeals said, “The individual mandate is unconstitutional because, under [a previous ruling, National Federation of Independent Business v Sebelius], it finds no constitutional footing in either the Interstate Commerce Clause or the Necessary and Proper Clause.”

The ruling upholds a December 2018 US District Court decision in which Judge Reed O’Connor found that the individual mandate that most Americans must have health insurance or pay a fine was unconstitutional and that without it the ACA itself was invalid.

In sending the case back to a Texas district court, however, the federal panel is asking for a central question to be resolved: Whether the individual mandate is “severable” from the rest of the law, while the rest of the law can be left intact.

If the district court eventually decides that the individual mandate cannot be severed from the rest of the ACA, the entire law will likely be ruled invalid, and some 24 million Americans could lose health coverage.

“Today’s ruling is the result of the Trump administration and congressional Republicans attempting to make dangerous health policy using the courts since they failed to succeed in Congress,” House Ways and Means Committee Chairman Richard E. Neal (D-Mass.) said in a statement. “This is a blow to our nation’s health care system and the millions of Americans who have gained coverage and protections under the Affordable Care Act. Democrats will continue to fight to protect Americans’ access to quality, affordable care.”

Some groups are applauding the decision, though. The Citizens’ Council for Health Freedom (CCHF), which filed an amicus brief with the Fifth Circuit arguing against the ACA, said it wants more.

“We are pleased with the Fifth Circuit Court of Appeals ruling, but it didn’t go far enough,” said Twila Brase, president and cofounder of CCHF, in a statement. “The individual mandate cannot be severed from the rest of the 2,700-page Affordable Care Act, thus the court should have ruled that the entire law is invalid, as the lower district court found.

“As the Court notes in the first paragraph of the ruling, we argued in our Amicus Brief, filed jointly with the Association of American Physicians and Surgeons, that the Act ‘has deprived patients nationwide of a competitive market for affordable high-deductible health insurance,’ leaving ‘patients with no alternative to ... skyrocketing premiums,’ “ Ms. Brase added. “Sending it back to the lower court, which already ruled the right way, continues to deprive citizens and patients of the affordable coverage that freedom from Obamacare would bring.”
 

Future uncertain

The ruling in Texas v Azar is not a surprise because, during oral arguments in July, as reported by Medscape Medical News, at least two of the three judges – Jennifer Walker Elrod, appointed by President George W. Bush in 2007, and Kurt Engelhardt, appointed by President Donald J. Trump in 2018 – appeared to be more receptive to the arguments of a group of 18 Republican states and two individuals seeking to invalidate the ACA.

Judge Carolyn Dineen King, appointed by President Jimmy Carter in 1979, did not comment during the hearing.

The Trump administration chose not to defend the ACA, but it does not seem entirely prepared for what might happen if the law is overturned. In a briefing before the Fifth Circuit hearing, the administration argued that, if ultimately the law is ruled unconstitutional, it should be struck down only in the states seeking to overturn the law.

“A lot of this has to get sorted out – it’s complicated,” said August E. Flentje, a U.S. Department of Justice lawyer, at the oral arguments in July.

For now, though, the ACA remains.

“In 2012, the Supreme Court upheld Obamacare, despite serious constitutional issues with the federal government forcing Americans to purchase a product from a private company. Until an ultimate decision is made by the Supreme Court or Congress decides otherwise, the Affordable Care Act will remain the law of the land,” Senate Finance Committee Chairman Chuck Grassley (R-Iowa), said in a statement.

And those who have led the court battle to keep the ACA intact plan to keep fighting. “For now, the President got the gift he wanted – uncertainty in the health care system and a pathway to repeal – so that the health care that seniors, workers, and families secured under the Affordable Care Act can be yanked from under them. This decision could take us to a dangerous and irresponsible place, not just for the 133 million Americans with pre-existing conditions, but for our seniors who use Medicare, our children under the age of 26, and the 20 million additional Americans covered directly through the ACA marketplace. California will move swiftly to challenge this decision because this could mean the difference between life and death for so many Americans and their families,” California Attorney General Xavier Becerra said in a statement.

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

A federal appeals court ruled Dec. 18 that the individual mandate of the Affordable Care Act (ACA) is unconstitutional, but the panel sent the case back to a lower court to decide how much of the remainder of the law could topple along with it.

The three-judge panel of the New Orleans-based U.S. Fifth Circuit Court of Appeals said, “The individual mandate is unconstitutional because, under [a previous ruling, National Federation of Independent Business v Sebelius], it finds no constitutional footing in either the Interstate Commerce Clause or the Necessary and Proper Clause.”

The ruling upholds a December 2018 US District Court decision in which Judge Reed O’Connor found that the individual mandate that most Americans must have health insurance or pay a fine was unconstitutional and that without it the ACA itself was invalid.

In sending the case back to a Texas district court, however, the federal panel is asking for a central question to be resolved: Whether the individual mandate is “severable” from the rest of the law, while the rest of the law can be left intact.

If the district court eventually decides that the individual mandate cannot be severed from the rest of the ACA, the entire law will likely be ruled invalid, and some 24 million Americans could lose health coverage.

“Today’s ruling is the result of the Trump administration and congressional Republicans attempting to make dangerous health policy using the courts since they failed to succeed in Congress,” House Ways and Means Committee Chairman Richard E. Neal (D-Mass.) said in a statement. “This is a blow to our nation’s health care system and the millions of Americans who have gained coverage and protections under the Affordable Care Act. Democrats will continue to fight to protect Americans’ access to quality, affordable care.”

Some groups are applauding the decision, though. The Citizens’ Council for Health Freedom (CCHF), which filed an amicus brief with the Fifth Circuit arguing against the ACA, said it wants more.

“We are pleased with the Fifth Circuit Court of Appeals ruling, but it didn’t go far enough,” said Twila Brase, president and cofounder of CCHF, in a statement. “The individual mandate cannot be severed from the rest of the 2,700-page Affordable Care Act, thus the court should have ruled that the entire law is invalid, as the lower district court found.

“As the Court notes in the first paragraph of the ruling, we argued in our Amicus Brief, filed jointly with the Association of American Physicians and Surgeons, that the Act ‘has deprived patients nationwide of a competitive market for affordable high-deductible health insurance,’ leaving ‘patients with no alternative to ... skyrocketing premiums,’ “ Ms. Brase added. “Sending it back to the lower court, which already ruled the right way, continues to deprive citizens and patients of the affordable coverage that freedom from Obamacare would bring.”
 

Future uncertain

The ruling in Texas v Azar is not a surprise because, during oral arguments in July, as reported by Medscape Medical News, at least two of the three judges – Jennifer Walker Elrod, appointed by President George W. Bush in 2007, and Kurt Engelhardt, appointed by President Donald J. Trump in 2018 – appeared to be more receptive to the arguments of a group of 18 Republican states and two individuals seeking to invalidate the ACA.

Judge Carolyn Dineen King, appointed by President Jimmy Carter in 1979, did not comment during the hearing.

The Trump administration chose not to defend the ACA, but it does not seem entirely prepared for what might happen if the law is overturned. In a briefing before the Fifth Circuit hearing, the administration argued that, if ultimately the law is ruled unconstitutional, it should be struck down only in the states seeking to overturn the law.

“A lot of this has to get sorted out – it’s complicated,” said August E. Flentje, a U.S. Department of Justice lawyer, at the oral arguments in July.

For now, though, the ACA remains.

“In 2012, the Supreme Court upheld Obamacare, despite serious constitutional issues with the federal government forcing Americans to purchase a product from a private company. Until an ultimate decision is made by the Supreme Court or Congress decides otherwise, the Affordable Care Act will remain the law of the land,” Senate Finance Committee Chairman Chuck Grassley (R-Iowa), said in a statement.

And those who have led the court battle to keep the ACA intact plan to keep fighting. “For now, the President got the gift he wanted – uncertainty in the health care system and a pathway to repeal – so that the health care that seniors, workers, and families secured under the Affordable Care Act can be yanked from under them. This decision could take us to a dangerous and irresponsible place, not just for the 133 million Americans with pre-existing conditions, but for our seniors who use Medicare, our children under the age of 26, and the 20 million additional Americans covered directly through the ACA marketplace. California will move swiftly to challenge this decision because this could mean the difference between life and death for so many Americans and their families,” California Attorney General Xavier Becerra said in a statement.

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

Radiation therapy should be the primary treatment for patients with basal cell carcinoma and cutaneous squamous cell carcinoma who are not candidates for surgery, according to a new guideline from an American Society for Radiation Oncology task force.

“We hope that the dermatology community will find this guideline helpful, especially when it comes to defining clinical and pathological characteristics that may necessitate a discussion about the merits of postoperative radiation therapy,” said lead author Anna Likhacheva, MD, of the Sutter Medical Center in Sacramento, Calif., in an email. The guideline was published in Practical Radiation Oncology.

To address five key questions in regard to radiation therapy (RT) for the two most common skin cancers, the American Society for Radiation Oncology convened a task force of radiation, medical, and surgical oncologists; dermatopathologists; a radiation oncology resident; a medical physicist; and a dermatologist. They reviewed studies of adults with nonmetastatic, invasive basal cell carcinoma (BCC) or cutaneous squamous cell carcinoma (cSCC) that were published between May 1998 and June 2018, with the caveat that “there are limited, well-conducted modern randomized trials” in this area. As such, the majority of the recommendations have low to moderate quality of evidence designations.

“The conspicuous lack of prospective and randomized data should serve as a reminder to open clinical trials and collect outcomes data in a prospective fashion,” added Dr. Likhacheva, noting that “improving the quality of data on this topic will ultimately serve our common goal of improving patient outcomes.”

Their first recommendation was to strongly consider definitive RT as an alternative to surgery for BCC and cSCC, especially in areas where a surgical procedure would potentially compromise function or cosmesis. However, they did discourage its use in patients with genetic conditions associated with increased radiosensitivity.

Their second recommendation was to strongly consider postoperative radiation therapy for clinically or radiologically apparent gross perineural spread. They also strongly recommended PORT for cSCC patients with close or positive margins, with T3 or T4 tumors, or with desmoplastic or infiltrative tumors.

Their third recommendation was to strongly consider therapeutic lymphadenectomy followed by adjuvant RT in patients with cSCC or BCC that has metastasized to the regional lymph nodes. They also recommended definitive RT in medically inoperable patients with the same metastasized cSCC or BCC. In addition, patients with BCC or cSCC undergoing adjuvant RT after therapeutic lymphadenectomy were recommended a dose of 6,000-6,600 cGy, while patients with cSCC undergoing elective RT without a lymphadenectomy were recommended a dose of 5,000-5,400 cGy.

Their fourth recommendation focused on techniques and dose-fractionation schedules for RT in the definitive or postoperative setting. For patients with BCC and cSCC receiving definitive RT, the biologically effective dose (BED₁₀) range for conventional fractionation – defined as 180-200 cGy/fraction – should be 70-93.5 and the BED₁₀ range for hypofractionation – defined as 210-500 cGy/fraction – should be 56-88. For patients with BCC and cSCC receiving postoperative RT, the BED₁₀ range for conventional fractionation should be 59.5-79.2 and the BED₁₀ range for hypofractionation should be 56-70.2.

Finally, their fifth recommendation was to not add concurrent carboplatin to adjuvant RT in patients with resected, locally advanced cSCC. They also conditionally recommended adding concurrent drug therapies to definitive RT in patients with unresected, locally advanced cSCC.

Several of the authors reported receiving honoraria and travel expenses from medical and pharmaceutical companies, along with serving on their advisory boards. The others reported no conflicts of interest.

SOURCE: Likhacheva A et al. Pract Radiat Oncol. 2019 Dec 9. doi: 10.1016/j.prro.2019.10.014.

Radiation therapy should be the primary treatment for patients with basal cell carcinoma and cutaneous squamous cell carcinoma who are not candidates for surgery, according to a new guideline from an American Society for Radiation Oncology task force.

“We hope that the dermatology community will find this guideline helpful, especially when it comes to defining clinical and pathological characteristics that may necessitate a discussion about the merits of postoperative radiation therapy,” said lead author Anna Likhacheva, MD, of the Sutter Medical Center in Sacramento, Calif., in an email. The guideline was published in Practical Radiation Oncology.

To address five key questions in regard to radiation therapy (RT) for the two most common skin cancers, the American Society for Radiation Oncology convened a task force of radiation, medical, and surgical oncologists; dermatopathologists; a radiation oncology resident; a medical physicist; and a dermatologist. They reviewed studies of adults with nonmetastatic, invasive basal cell carcinoma (BCC) or cutaneous squamous cell carcinoma (cSCC) that were published between May 1998 and June 2018, with the caveat that “there are limited, well-conducted modern randomized trials” in this area. As such, the majority of the recommendations have low to moderate quality of evidence designations.

“The conspicuous lack of prospective and randomized data should serve as a reminder to open clinical trials and collect outcomes data in a prospective fashion,” added Dr. Likhacheva, noting that “improving the quality of data on this topic will ultimately serve our common goal of improving patient outcomes.”

Their first recommendation was to strongly consider definitive RT as an alternative to surgery for BCC and cSCC, especially in areas where a surgical procedure would potentially compromise function or cosmesis. However, they did discourage its use in patients with genetic conditions associated with increased radiosensitivity.

Their second recommendation was to strongly consider postoperative radiation therapy for clinically or radiologically apparent gross perineural spread. They also strongly recommended PORT for cSCC patients with close or positive margins, with T3 or T4 tumors, or with desmoplastic or infiltrative tumors.

Their third recommendation was to strongly consider therapeutic lymphadenectomy followed by adjuvant RT in patients with cSCC or BCC that has metastasized to the regional lymph nodes. They also recommended definitive RT in medically inoperable patients with the same metastasized cSCC or BCC. In addition, patients with BCC or cSCC undergoing adjuvant RT after therapeutic lymphadenectomy were recommended a dose of 6,000-6,600 cGy, while patients with cSCC undergoing elective RT without a lymphadenectomy were recommended a dose of 5,000-5,400 cGy.

Their fourth recommendation focused on techniques and dose-fractionation schedules for RT in the definitive or postoperative setting. For patients with BCC and cSCC receiving definitive RT, the biologically effective dose (BED₁₀) range for conventional fractionation – defined as 180-200 cGy/fraction – should be 70-93.5 and the BED₁₀ range for hypofractionation – defined as 210-500 cGy/fraction – should be 56-88. For patients with BCC and cSCC receiving postoperative RT, the BED₁₀ range for conventional fractionation should be 59.5-79.2 and the BED₁₀ range for hypofractionation should be 56-70.2.

Finally, their fifth recommendation was to not add concurrent carboplatin to adjuvant RT in patients with resected, locally advanced cSCC. They also conditionally recommended adding concurrent drug therapies to definitive RT in patients with unresected, locally advanced cSCC.

Several of the authors reported receiving honoraria and travel expenses from medical and pharmaceutical companies, along with serving on their advisory boards. The others reported no conflicts of interest.

SOURCE: Likhacheva A et al. Pract Radiat Oncol. 2019 Dec 9. doi: 10.1016/j.prro.2019.10.014.

Radiation therapy should be the primary treatment for patients with basal cell carcinoma and cutaneous squamous cell carcinoma who are not candidates for surgery, according to a new guideline from an American Society for Radiation Oncology task force.

“We hope that the dermatology community will find this guideline helpful, especially when it comes to defining clinical and pathological characteristics that may necessitate a discussion about the merits of postoperative radiation therapy,” said lead author Anna Likhacheva, MD, of the Sutter Medical Center in Sacramento, Calif., in an email. The guideline was published in Practical Radiation Oncology.

To address five key questions in regard to radiation therapy (RT) for the two most common skin cancers, the American Society for Radiation Oncology convened a task force of radiation, medical, and surgical oncologists; dermatopathologists; a radiation oncology resident; a medical physicist; and a dermatologist. They reviewed studies of adults with nonmetastatic, invasive basal cell carcinoma (BCC) or cutaneous squamous cell carcinoma (cSCC) that were published between May 1998 and June 2018, with the caveat that “there are limited, well-conducted modern randomized trials” in this area. As such, the majority of the recommendations have low to moderate quality of evidence designations.

“The conspicuous lack of prospective and randomized data should serve as a reminder to open clinical trials and collect outcomes data in a prospective fashion,” added Dr. Likhacheva, noting that “improving the quality of data on this topic will ultimately serve our common goal of improving patient outcomes.”

Their first recommendation was to strongly consider definitive RT as an alternative to surgery for BCC and cSCC, especially in areas where a surgical procedure would potentially compromise function or cosmesis. However, they did discourage its use in patients with genetic conditions associated with increased radiosensitivity.

Their second recommendation was to strongly consider postoperative radiation therapy for clinically or radiologically apparent gross perineural spread. They also strongly recommended PORT for cSCC patients with close or positive margins, with T3 or T4 tumors, or with desmoplastic or infiltrative tumors.

Their third recommendation was to strongly consider therapeutic lymphadenectomy followed by adjuvant RT in patients with cSCC or BCC that has metastasized to the regional lymph nodes. They also recommended definitive RT in medically inoperable patients with the same metastasized cSCC or BCC. In addition, patients with BCC or cSCC undergoing adjuvant RT after therapeutic lymphadenectomy were recommended a dose of 6,000-6,600 cGy, while patients with cSCC undergoing elective RT without a lymphadenectomy were recommended a dose of 5,000-5,400 cGy.

Their fourth recommendation focused on techniques and dose-fractionation schedules for RT in the definitive or postoperative setting. For patients with BCC and cSCC receiving definitive RT, the biologically effective dose (BED₁₀) range for conventional fractionation – defined as 180-200 cGy/fraction – should be 70-93.5 and the BED₁₀ range for hypofractionation – defined as 210-500 cGy/fraction – should be 56-88. For patients with BCC and cSCC receiving postoperative RT, the BED₁₀ range for conventional fractionation should be 59.5-79.2 and the BED₁₀ range for hypofractionation should be 56-70.2.

Finally, their fifth recommendation was to not add concurrent carboplatin to adjuvant RT in patients with resected, locally advanced cSCC. They also conditionally recommended adding concurrent drug therapies to definitive RT in patients with unresected, locally advanced cSCC.

Several of the authors reported receiving honoraria and travel expenses from medical and pharmaceutical companies, along with serving on their advisory boards. The others reported no conflicts of interest.

SOURCE: Likhacheva A et al. Pract Radiat Oncol. 2019 Dec 9. doi: 10.1016/j.prro.2019.10.014.

The Department of Health & Human Services is taking the first steps in allowing drugs to be imported into the United States.

Wikimedia Commons/WWsgConnect/CC-SA 4.0

HHS proposes to offer two different pathways for importation: One allowing states to design programs to import certain drugs directly from Canada and another allowing manufacturers to obtain a new National Drug Code (NDC) number to import their own Food and Drug Administration–approved products manufactured outside of the United States.

“The importation proposals we are rolling out ... are a historic step forward in efforts to bring down drug prices and out-of-pocket costs,” HHS Secretary Alex Azar said during a Dec. 17, 2019, press conference. “New pathways for importation can move us toward a more open and competitive marketplace that supplies American patients with safe, effective, affordable prescription drugs.”

The proposals were made public on Dec. 18, the day the House Rules committee was scheduled to vote on impeaching President Trump.

He emphasized that these proposals “are both important steps in advancing the FDA’s safe-importation action plan, [which] aims to insure that importation is done in a way that prioritizes safety and includes elements to help insure importation does not put patients or the U.S. drug supply chain at risk.”

The pathway for states to import drugs from Canada will be proposed through the federal regulatory process. The notice of proposed rulemaking, which implements authority for FDA regulation of importation granted in the Medicare Modernization Act of 2003, will outline a process by which states, potentially working with wholesalers and/or pharmacies, will submit proposals for FDA review and approval on how they would implement an importation program.

Only certain drugs would be eligible for importation from Canada under this proposal. The drugs would need to be approved in Canada and, except for Canadian labeling, need to meet the conditions of an FDA-approved new drug application or abbreviated new drug application.

Controlled substances, biologics, intravenously injected drugs, drugs with a risk evaluation and management strategy, and drugs injected into the spinal column or eye would be excluded from importation.

Drugs coming in from Canada would be relabeled with U.S.-approved labels and would be subject to testing to ensure they are authentic, not degraded, and compliant with U.S. standards.

States would be required to show that importing drugs poses no additional risk in public health and safety and it would result in the reduction of costs, according to information provided by HHS.

Many of the most expensive drugs, as well as insulins, would not be eligible for importation under this pathway, Mr. Azar acknowledged, adding that “I would envision that as we demonstrate the safety as well as the cost savings from this pathway, [this could serve as] a pilot and a proof of concept that Congress could then look to and potentially take up for more complex molecules that involve cold-chain storage and more complex distribution channels.”

The proposed regulations do not offer any estimates on how much savings could be achieved. He said that there is no way to estimate which states might develop importation plans and how those plans might work.

The second proposed pathway would involve FDA guidance to manufacturers allowing them to import their own FDA-approved products manufactured abroad. Under this proposal, there would be no restriction on which type or kind of FDA-approved product to be imported.

“The FDA has become aware that manufacturers of some brand-name drugs want to offer their drugs at lower costs in the U.S. market but, due to certain challenges in the private market, are not readily [able] to do so without obtaining a different national drug code for their drugs,” Adm. Brett Giroir, MD, HHS assistant secretary for health, said during the press conference.

Obtaining a separate NDC for imported drugs could address the challenges, particularly those posed by the incentives to raise list prices and offer higher rebates to pharmacy benefit managers, Mr. Azar said.

The draft guidance outlines procedures manufacturers could follow to get that NDC for those products and how manufacturers can demonstrate that these products meet U.S. regulatory standards. Products imported in this pathway could be made available to patients in hospitals, physician offices, and pharmacies. Generic drugs are not part of this guidance, but the proposed guidance asked for feedback on whether a similar approach is needed for generic products.

“This would potentially allow for the sale of these drugs at lower prices than currently offered to American consumers, giving drugmakers new flexibility to reduce list prices,” Mr. Azar said.

The proposed regulation on state-level importation will have a 75-day comment period from the day it is published in the Federal Register, and Mr. Azar said that the FDA is committing resources to getting the comments analyzed and reflected in the final rule.

“We will be moving as quickly as we possibly can,” Mr. Azar said, adding that the FDA guidance to manufacturers may move more quickly through its approval process because it is not a formal rule.

[email protected]

The Department of Health & Human Services is taking the first steps in allowing drugs to be imported into the United States.

Wikimedia Commons/WWsgConnect/CC-SA 4.0

HHS proposes to offer two different pathways for importation: One allowing states to design programs to import certain drugs directly from Canada and another allowing manufacturers to obtain a new National Drug Code (NDC) number to import their own Food and Drug Administration–approved products manufactured outside of the United States.

“The importation proposals we are rolling out ... are a historic step forward in efforts to bring down drug prices and out-of-pocket costs,” HHS Secretary Alex Azar said during a Dec. 17, 2019, press conference. “New pathways for importation can move us toward a more open and competitive marketplace that supplies American patients with safe, effective, affordable prescription drugs.”

The proposals were made public on Dec. 18, the day the House Rules committee was scheduled to vote on impeaching President Trump.

He emphasized that these proposals “are both important steps in advancing the FDA’s safe-importation action plan, [which] aims to insure that importation is done in a way that prioritizes safety and includes elements to help insure importation does not put patients or the U.S. drug supply chain at risk.”

The pathway for states to import drugs from Canada will be proposed through the federal regulatory process. The notice of proposed rulemaking, which implements authority for FDA regulation of importation granted in the Medicare Modernization Act of 2003, will outline a process by which states, potentially working with wholesalers and/or pharmacies, will submit proposals for FDA review and approval on how they would implement an importation program.

Only certain drugs would be eligible for importation from Canada under this proposal. The drugs would need to be approved in Canada and, except for Canadian labeling, need to meet the conditions of an FDA-approved new drug application or abbreviated new drug application.

Controlled substances, biologics, intravenously injected drugs, drugs with a risk evaluation and management strategy, and drugs injected into the spinal column or eye would be excluded from importation.

Drugs coming in from Canada would be relabeled with U.S.-approved labels and would be subject to testing to ensure they are authentic, not degraded, and compliant with U.S. standards.

States would be required to show that importing drugs poses no additional risk in public health and safety and it would result in the reduction of costs, according to information provided by HHS.

Many of the most expensive drugs, as well as insulins, would not be eligible for importation under this pathway, Mr. Azar acknowledged, adding that “I would envision that as we demonstrate the safety as well as the cost savings from this pathway, [this could serve as] a pilot and a proof of concept that Congress could then look to and potentially take up for more complex molecules that involve cold-chain storage and more complex distribution channels.”

The proposed regulations do not offer any estimates on how much savings could be achieved. He said that there is no way to estimate which states might develop importation plans and how those plans might work.

The second proposed pathway would involve FDA guidance to manufacturers allowing them to import their own FDA-approved products manufactured abroad. Under this proposal, there would be no restriction on which type or kind of FDA-approved product to be imported.

“The FDA has become aware that manufacturers of some brand-name drugs want to offer their drugs at lower costs in the U.S. market but, due to certain challenges in the private market, are not readily [able] to do so without obtaining a different national drug code for their drugs,” Adm. Brett Giroir, MD, HHS assistant secretary for health, said during the press conference.

Obtaining a separate NDC for imported drugs could address the challenges, particularly those posed by the incentives to raise list prices and offer higher rebates to pharmacy benefit managers, Mr. Azar said.

The draft guidance outlines procedures manufacturers could follow to get that NDC for those products and how manufacturers can demonstrate that these products meet U.S. regulatory standards. Products imported in this pathway could be made available to patients in hospitals, physician offices, and pharmacies. Generic drugs are not part of this guidance, but the proposed guidance asked for feedback on whether a similar approach is needed for generic products.

“This would potentially allow for the sale of these drugs at lower prices than currently offered to American consumers, giving drugmakers new flexibility to reduce list prices,” Mr. Azar said.

The proposed regulation on state-level importation will have a 75-day comment period from the day it is published in the Federal Register, and Mr. Azar said that the FDA is committing resources to getting the comments analyzed and reflected in the final rule.

“We will be moving as quickly as we possibly can,” Mr. Azar said, adding that the FDA guidance to manufacturers may move more quickly through its approval process because it is not a formal rule.

[email protected]

The Department of Health & Human Services is taking the first steps in allowing drugs to be imported into the United States.

Wikimedia Commons/WWsgConnect/CC-SA 4.0

HHS proposes to offer two different pathways for importation: One allowing states to design programs to import certain drugs directly from Canada and another allowing manufacturers to obtain a new National Drug Code (NDC) number to import their own Food and Drug Administration–approved products manufactured outside of the United States.

“The importation proposals we are rolling out ... are a historic step forward in efforts to bring down drug prices and out-of-pocket costs,” HHS Secretary Alex Azar said during a Dec. 17, 2019, press conference. “New pathways for importation can move us toward a more open and competitive marketplace that supplies American patients with safe, effective, affordable prescription drugs.”

The proposals were made public on Dec. 18, the day the House Rules committee was scheduled to vote on impeaching President Trump.

He emphasized that these proposals “are both important steps in advancing the FDA’s safe-importation action plan, [which] aims to insure that importation is done in a way that prioritizes safety and includes elements to help insure importation does not put patients or the U.S. drug supply chain at risk.”

The pathway for states to import drugs from Canada will be proposed through the federal regulatory process. The notice of proposed rulemaking, which implements authority for FDA regulation of importation granted in the Medicare Modernization Act of 2003, will outline a process by which states, potentially working with wholesalers and/or pharmacies, will submit proposals for FDA review and approval on how they would implement an importation program.

Only certain drugs would be eligible for importation from Canada under this proposal. The drugs would need to be approved in Canada and, except for Canadian labeling, need to meet the conditions of an FDA-approved new drug application or abbreviated new drug application.

Controlled substances, biologics, intravenously injected drugs, drugs with a risk evaluation and management strategy, and drugs injected into the spinal column or eye would be excluded from importation.

Drugs coming in from Canada would be relabeled with U.S.-approved labels and would be subject to testing to ensure they are authentic, not degraded, and compliant with U.S. standards.

States would be required to show that importing drugs poses no additional risk in public health and safety and it would result in the reduction of costs, according to information provided by HHS.

Many of the most expensive drugs, as well as insulins, would not be eligible for importation under this pathway, Mr. Azar acknowledged, adding that “I would envision that as we demonstrate the safety as well as the cost savings from this pathway, [this could serve as] a pilot and a proof of concept that Congress could then look to and potentially take up for more complex molecules that involve cold-chain storage and more complex distribution channels.”

The proposed regulations do not offer any estimates on how much savings could be achieved. He said that there is no way to estimate which states might develop importation plans and how those plans might work.

The second proposed pathway would involve FDA guidance to manufacturers allowing them to import their own FDA-approved products manufactured abroad. Under this proposal, there would be no restriction on which type or kind of FDA-approved product to be imported.

“The FDA has become aware that manufacturers of some brand-name drugs want to offer their drugs at lower costs in the U.S. market but, due to certain challenges in the private market, are not readily [able] to do so without obtaining a different national drug code for their drugs,” Adm. Brett Giroir, MD, HHS assistant secretary for health, said during the press conference.

Obtaining a separate NDC for imported drugs could address the challenges, particularly those posed by the incentives to raise list prices and offer higher rebates to pharmacy benefit managers, Mr. Azar said.

The draft guidance outlines procedures manufacturers could follow to get that NDC for those products and how manufacturers can demonstrate that these products meet U.S. regulatory standards. Products imported in this pathway could be made available to patients in hospitals, physician offices, and pharmacies. Generic drugs are not part of this guidance, but the proposed guidance asked for feedback on whether a similar approach is needed for generic products.

“This would potentially allow for the sale of these drugs at lower prices than currently offered to American consumers, giving drugmakers new flexibility to reduce list prices,” Mr. Azar said.

The proposed regulation on state-level importation will have a 75-day comment period from the day it is published in the Federal Register, and Mr. Azar said that the FDA is committing resources to getting the comments analyzed and reflected in the final rule.

“We will be moving as quickly as we possibly can,” Mr. Azar said, adding that the FDA guidance to manufacturers may move more quickly through its approval process because it is not a formal rule.

[email protected]

PHILADELPHIA – Use of the Impella ventricular-assist device in patients with cardiogenic shock having percutaneous coronary interventions (PCI) has increased rapidly since its approval in 2008, but two studies comparing it with intra-aortic balloon pumps in PCI patients have raised questions about the safety, effectiveness, and cost of the ventricular-assist device, according to results of two studies presented at the American Heart Association scientific sessions.

The results of an observational analysis of 48,306 patients and a national real-world study of 28,304 patients may not be telling the complete story of the utility of ventricular assist in patients requiring mechanical circulatory support (MCS), one interventional cardiologist said in an interview. “It’s concerning; it’s sobering,” said Ranya N. Sweis, MD, of Northwestern University, Chicago. However, the data didn’t parse out patients who would have been routed to palliative care and otherwise wouldn’t have been candidates for PCI without MCS.

“What I take from it is that we need to get more randomized data,” she said. “Who are the patients that were doing worse? Who are the patients who really needed the Impella support for the PCI after cardiogenic shock?”

In the observational study, Amit P. Amin, MD, of Washington University, St. Louis, said that the use of MCS devices increased steadily to 32% of all PCI patients receiving MCS from 2008 to 2016 while use of intra-aortic balloon pump (IABP) declined, but that Impella was less likely to be used in critically ill patients. The study analyzed patients in the Premier Healthcare Database who had PCI with MCS at 432 hospitals from 2004 to 2016.

Outcomes in what Dr. Amin called “the Impella era,” showed significantly higher risks for death, acute kidney injury, and stroke, with odds ratios of 1.17, 1.91 and 3.34, respectively (P less than .001 for all). In the patient-level comparison of Impella versus IABP, Impella had a 24% higher risk of death (P less than .0001), 10% for bleeding (P = .0445), 8% for acute kidney injury (P = .0521) and 34% for stroke (P less than .0001). The findings were published simultaneously with the presentation (Circulation. 2019 Nov 17. doi: 10.1161/CIRCULATIONAHA.119.044007)

“The total length of stay, as well as the ICU length of stay, were actually lower with Impella use, by approximately a half day to 1 day,” Dr. Amin said. “Despite that, the total costs were approximately $15,000.”

Yet, the study found wide variation in the use of Impella among hospitals, some doing no cases with the device and others all of them, Dr. Amin said. The risk analysis also found wide variations in outcomes across hospitals using Impella. “We saw a 2.5-fold variation in bleeding across hospitals and a 1.5-fold variation in acute kidney injury, stroke and death,” he noted. The study found less variation in hospital stays and total cost of Impella, “perhaps related to the uniformly high device acquisition costs.”

“These data underscore the need for defining the appropriate use of mechanical circulatory support in patients undergoing PCI,” Dr. Amin said.

Dr. Sweis wasn’t surprised by the cost findings. “New technology is going to cost more,” she said in an interview. “I’m actually surprised that the cost wasn’t more significantly different just knowing the cost of some of these devices.

Patients who require MCS represent a small portion of PCI cases: 2%, according to Dr. Sweis. “It’s not like all PCI has increased because of MCS, and there’s a potential improvement in the length of stay so there are going to be cost savings that way.”

The national real-world study that Sanket S. Dhruva, MD, MHS, of the University of California San Francisco, reported on focused on Impella and IABP in PCI patients with acute MI complicated by cardiogenic shock (CS). The study used outcomes of patients with AMI-CS who had PCI from October 2015 to December 2017 in the National Cardiovascular Data Registry’s CathPCI and Chest Pain–MI registries. An estimated 4%-12% of AMIs present with CS.

Most patients in the study population had medical therapy only, but this study focused on the 1,768 who had Impella only and the 8,471 who had IABP only. The rates of in-hospital death and bleeding were 34.1% 16% in the IABP group, and 45% and 31.3% in the Impella group, Dr. Dhruva said. In this study population, the rate of Impella use increased from 3.5% in 2015 to 8.7% by the end of 2017 (P less than .001).

Dr. Dhruva acknowledged a number of limitations to the study findings, including residual confounding. However, the “robust propensity match” of 95% of the Impella-only patients and the results were consistent across multiple sensitivity analyses. “There may have been questions about the clinical severity of AMI-CS patients in the NCDR Registry,” he said. “However, the registry definition is similar to that used in the trials.”

The trial also failed to distinguish between the different types of Impella devices, but the results mostly pertain to the Impella 2.5 and CP because the 5.0 device requires a surgical cutdown, and the study excluded patients who received multiple devices.

“Better evidence and guidance are needed regarding the optimal management of patients with AMI-CS as well as the role of mechanical circulatory support devices in general and Impella in particular,” he said, adding that Impella has been on the U.S. market since 2008, but with limited randomized clinical trial evidence in cardiogenic shock.

The study population of patient’s with CS is “only a piece of the puzzle,” Dr. Sweis said. “We know that there are sick hearts that aren’t in shock right now, but you’re going to do triple-vessel intervention and use atherectomy. Those patients would not do very well during the procedure itself and it may not even be offered to them if there weren’t support.”

Impella is not going away, Dr. Sweis said. “It provides an option that a patient wouldn’t otherwise have. This is really stressing to me that we need to get rid of that variability in the safety related to these devices.”

Dr. Amin disclosed financial relationships with Terumo and GE Healthcare. Dr. Dhruva had no financial relationships to disclose. The study was supported in part by a Center of Excellence in Regulatory Science and Innovation grant from the Food and Drug Administration and the American College of Cardiology’s National Cardiovascular Data Registry.

PHILADELPHIA – Use of the Impella ventricular-assist device in patients with cardiogenic shock having percutaneous coronary interventions (PCI) has increased rapidly since its approval in 2008, but two studies comparing it with intra-aortic balloon pumps in PCI patients have raised questions about the safety, effectiveness, and cost of the ventricular-assist device, according to results of two studies presented at the American Heart Association scientific sessions.

The results of an observational analysis of 48,306 patients and a national real-world study of 28,304 patients may not be telling the complete story of the utility of ventricular assist in patients requiring mechanical circulatory support (MCS), one interventional cardiologist said in an interview. “It’s concerning; it’s sobering,” said Ranya N. Sweis, MD, of Northwestern University, Chicago. However, the data didn’t parse out patients who would have been routed to palliative care and otherwise wouldn’t have been candidates for PCI without MCS.

“What I take from it is that we need to get more randomized data,” she said. “Who are the patients that were doing worse? Who are the patients who really needed the Impella support for the PCI after cardiogenic shock?”

In the observational study, Amit P. Amin, MD, of Washington University, St. Louis, said that the use of MCS devices increased steadily to 32% of all PCI patients receiving MCS from 2008 to 2016 while use of intra-aortic balloon pump (IABP) declined, but that Impella was less likely to be used in critically ill patients. The study analyzed patients in the Premier Healthcare Database who had PCI with MCS at 432 hospitals from 2004 to 2016.

Outcomes in what Dr. Amin called “the Impella era,” showed significantly higher risks for death, acute kidney injury, and stroke, with odds ratios of 1.17, 1.91 and 3.34, respectively (P less than .001 for all). In the patient-level comparison of Impella versus IABP, Impella had a 24% higher risk of death (P less than .0001), 10% for bleeding (P = .0445), 8% for acute kidney injury (P = .0521) and 34% for stroke (P less than .0001). The findings were published simultaneously with the presentation (Circulation. 2019 Nov 17. doi: 10.1161/CIRCULATIONAHA.119.044007)

“The total length of stay, as well as the ICU length of stay, were actually lower with Impella use, by approximately a half day to 1 day,” Dr. Amin said. “Despite that, the total costs were approximately $15,000.”

Yet, the study found wide variation in the use of Impella among hospitals, some doing no cases with the device and others all of them, Dr. Amin said. The risk analysis also found wide variations in outcomes across hospitals using Impella. “We saw a 2.5-fold variation in bleeding across hospitals and a 1.5-fold variation in acute kidney injury, stroke and death,” he noted. The study found less variation in hospital stays and total cost of Impella, “perhaps related to the uniformly high device acquisition costs.”

“These data underscore the need for defining the appropriate use of mechanical circulatory support in patients undergoing PCI,” Dr. Amin said.

Dr. Sweis wasn’t surprised by the cost findings. “New technology is going to cost more,” she said in an interview. “I’m actually surprised that the cost wasn’t more significantly different just knowing the cost of some of these devices.

Patients who require MCS represent a small portion of PCI cases: 2%, according to Dr. Sweis. “It’s not like all PCI has increased because of MCS, and there’s a potential improvement in the length of stay so there are going to be cost savings that way.”

The national real-world study that Sanket S. Dhruva, MD, MHS, of the University of California San Francisco, reported on focused on Impella and IABP in PCI patients with acute MI complicated by cardiogenic shock (CS). The study used outcomes of patients with AMI-CS who had PCI from October 2015 to December 2017 in the National Cardiovascular Data Registry’s CathPCI and Chest Pain–MI registries. An estimated 4%-12% of AMIs present with CS.

Most patients in the study population had medical therapy only, but this study focused on the 1,768 who had Impella only and the 8,471 who had IABP only. The rates of in-hospital death and bleeding were 34.1% 16% in the IABP group, and 45% and 31.3% in the Impella group, Dr. Dhruva said. In this study population, the rate of Impella use increased from 3.5% in 2015 to 8.7% by the end of 2017 (P less than .001).

Dr. Dhruva acknowledged a number of limitations to the study findings, including residual confounding. However, the “robust propensity match” of 95% of the Impella-only patients and the results were consistent across multiple sensitivity analyses. “There may have been questions about the clinical severity of AMI-CS patients in the NCDR Registry,” he said. “However, the registry definition is similar to that used in the trials.”

The trial also failed to distinguish between the different types of Impella devices, but the results mostly pertain to the Impella 2.5 and CP because the 5.0 device requires a surgical cutdown, and the study excluded patients who received multiple devices.

“Better evidence and guidance are needed regarding the optimal management of patients with AMI-CS as well as the role of mechanical circulatory support devices in general and Impella in particular,” he said, adding that Impella has been on the U.S. market since 2008, but with limited randomized clinical trial evidence in cardiogenic shock.

The study population of patient’s with CS is “only a piece of the puzzle,” Dr. Sweis said. “We know that there are sick hearts that aren’t in shock right now, but you’re going to do triple-vessel intervention and use atherectomy. Those patients would not do very well during the procedure itself and it may not even be offered to them if there weren’t support.”

Impella is not going away, Dr. Sweis said. “It provides an option that a patient wouldn’t otherwise have. This is really stressing to me that we need to get rid of that variability in the safety related to these devices.”

Dr. Amin disclosed financial relationships with Terumo and GE Healthcare. Dr. Dhruva had no financial relationships to disclose. The study was supported in part by a Center of Excellence in Regulatory Science and Innovation grant from the Food and Drug Administration and the American College of Cardiology’s National Cardiovascular Data Registry.

PHILADELPHIA – Use of the Impella ventricular-assist device in patients with cardiogenic shock having percutaneous coronary interventions (PCI) has increased rapidly since its approval in 2008, but two studies comparing it with intra-aortic balloon pumps in PCI patients have raised questions about the safety, effectiveness, and cost of the ventricular-assist device, according to results of two studies presented at the American Heart Association scientific sessions.

The results of an observational analysis of 48,306 patients and a national real-world study of 28,304 patients may not be telling the complete story of the utility of ventricular assist in patients requiring mechanical circulatory support (MCS), one interventional cardiologist said in an interview. “It’s concerning; it’s sobering,” said Ranya N. Sweis, MD, of Northwestern University, Chicago. However, the data didn’t parse out patients who would have been routed to palliative care and otherwise wouldn’t have been candidates for PCI without MCS.

“What I take from it is that we need to get more randomized data,” she said. “Who are the patients that were doing worse? Who are the patients who really needed the Impella support for the PCI after cardiogenic shock?”

In the observational study, Amit P. Amin, MD, of Washington University, St. Louis, said that the use of MCS devices increased steadily to 32% of all PCI patients receiving MCS from 2008 to 2016 while use of intra-aortic balloon pump (IABP) declined, but that Impella was less likely to be used in critically ill patients. The study analyzed patients in the Premier Healthcare Database who had PCI with MCS at 432 hospitals from 2004 to 2016.

Outcomes in what Dr. Amin called “the Impella era,” showed significantly higher risks for death, acute kidney injury, and stroke, with odds ratios of 1.17, 1.91 and 3.34, respectively (P less than .001 for all). In the patient-level comparison of Impella versus IABP, Impella had a 24% higher risk of death (P less than .0001), 10% for bleeding (P = .0445), 8% for acute kidney injury (P = .0521) and 34% for stroke (P less than .0001). The findings were published simultaneously with the presentation (Circulation. 2019 Nov 17. doi: 10.1161/CIRCULATIONAHA.119.044007)

“The total length of stay, as well as the ICU length of stay, were actually lower with Impella use, by approximately a half day to 1 day,” Dr. Amin said. “Despite that, the total costs were approximately $15,000.”

Yet, the study found wide variation in the use of Impella among hospitals, some doing no cases with the device and others all of them, Dr. Amin said. The risk analysis also found wide variations in outcomes across hospitals using Impella. “We saw a 2.5-fold variation in bleeding across hospitals and a 1.5-fold variation in acute kidney injury, stroke and death,” he noted. The study found less variation in hospital stays and total cost of Impella, “perhaps related to the uniformly high device acquisition costs.”

“These data underscore the need for defining the appropriate use of mechanical circulatory support in patients undergoing PCI,” Dr. Amin said.

Dr. Sweis wasn’t surprised by the cost findings. “New technology is going to cost more,” she said in an interview. “I’m actually surprised that the cost wasn’t more significantly different just knowing the cost of some of these devices.

Patients who require MCS represent a small portion of PCI cases: 2%, according to Dr. Sweis. “It’s not like all PCI has increased because of MCS, and there’s a potential improvement in the length of stay so there are going to be cost savings that way.”

The national real-world study that Sanket S. Dhruva, MD, MHS, of the University of California San Francisco, reported on focused on Impella and IABP in PCI patients with acute MI complicated by cardiogenic shock (CS). The study used outcomes of patients with AMI-CS who had PCI from October 2015 to December 2017 in the National Cardiovascular Data Registry’s CathPCI and Chest Pain–MI registries. An estimated 4%-12% of AMIs present with CS.

Most patients in the study population had medical therapy only, but this study focused on the 1,768 who had Impella only and the 8,471 who had IABP only. The rates of in-hospital death and bleeding were 34.1% 16% in the IABP group, and 45% and 31.3% in the Impella group, Dr. Dhruva said. In this study population, the rate of Impella use increased from 3.5% in 2015 to 8.7% by the end of 2017 (P less than .001).

Dr. Dhruva acknowledged a number of limitations to the study findings, including residual confounding. However, the “robust propensity match” of 95% of the Impella-only patients and the results were consistent across multiple sensitivity analyses. “There may have been questions about the clinical severity of AMI-CS patients in the NCDR Registry,” he said. “However, the registry definition is similar to that used in the trials.”

The trial also failed to distinguish between the different types of Impella devices, but the results mostly pertain to the Impella 2.5 and CP because the 5.0 device requires a surgical cutdown, and the study excluded patients who received multiple devices.

“Better evidence and guidance are needed regarding the optimal management of patients with AMI-CS as well as the role of mechanical circulatory support devices in general and Impella in particular,” he said, adding that Impella has been on the U.S. market since 2008, but with limited randomized clinical trial evidence in cardiogenic shock.

The study population of patient’s with CS is “only a piece of the puzzle,” Dr. Sweis said. “We know that there are sick hearts that aren’t in shock right now, but you’re going to do triple-vessel intervention and use atherectomy. Those patients would not do very well during the procedure itself and it may not even be offered to them if there weren’t support.”

Impella is not going away, Dr. Sweis said. “It provides an option that a patient wouldn’t otherwise have. This is really stressing to me that we need to get rid of that variability in the safety related to these devices.”

Dr. Amin disclosed financial relationships with Terumo and GE Healthcare. Dr. Dhruva had no financial relationships to disclose. The study was supported in part by a Center of Excellence in Regulatory Science and Innovation grant from the Food and Drug Administration and the American College of Cardiology’s National Cardiovascular Data Registry.

LOS ANGELES – In the opinion of Richard Pratley, MD, it’s time for diabetes treatment guidelines to evolve in light of accumulating data from cardiovascular outcome trials in type 2 diabetes.

“They have evolved for the general patient population, and this should apply to older individuals as well,” Dr. Pratley said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “My fear is, there is therapeutic nihilism, the idea that by the time someone is 75 years old, the horse is out of the barn and you’re not going to be able to impact outcomes with directed therapy. I don’t think that’s true. Our current treatment guidelines for the treatment of diabetes in older individuals remain focused on glycemic control. It’s not hyperglycemia that’s killing people; it’s heart disease and renal disease.”

According to data from the United Nations, about 12% of the global population is older than 60. By 2050, that number is expected to reach 20%, which will continue to drive an epidemic of diabetes in the near future. Dr. Pratley, medical director of AdventHealth Diabetes Institute in Orlando, pointed out that diabetes in older individuals is not a homogeneous condition. “There are many people in my clinic who had type 1 diabetes diagnosed as kids, but I also have patients who have adult-onset type 1 diabetes,” he said. “We also have type 2 patients who can be diagnosed in their 20s, 30s, or 40s, and there are people who are diagnosed in their 70s and 80s. Now we are learning that there are different subtypes of diabetes; so even type 2 diabetes is not a homogeneous condition. There are people who are more insulin resistant or have more of an insulin secretory defect, and there’s a special type of older-onset type 2 diabetes. When you consider all this in talking about diabetes treatments, about 30% of patients in the United States are diagnosed [when they are] over the age of 60, so this is an ongoing issue.”

Older adults with diabetes may have longstanding diabetes with associated microvascular and macrovascular complications, he continued, or they may have newly diagnosed diabetes with evidence of end organ complications at the time of presentation. Or, they may have newly diagnosed diabetes without evidence of complications. “Does this matter? It does,” Dr. Pratley said. “The things we worry about with all patients with diabetes are the microvascular complications, but I would argue that the macrovascular complications, particularly diabetic nephropathy, are things we should have a laser focus on, because they have high morbidity and mortality, especially in older individuals.”

There are more than 28 cardiovascular outcomes trials in patients with type 2 diabetes ongoing or completed, and involving eight classes of medications, with more than 200,000 planned participants, Dr. Pratley said. Of those participants, 90,000 are older than 65 years, and 30,000 are older than 75 years. “This is great,” he said. “Not only do these cardiovascular outcome studies give us a lot of information about the safety and efficacy of these drugs in the general population, we can now dig in to this specific patient population.” For example, in cardiovascular outcomes trials with dipeptidyl peptidase–4 (DPP-4) inhibitors, the mean age of patients was 65. About half of the patients were older than 65, and 10%-14% were older than 75.

Investigators in the SAVOR-TIMI 53 trial examined age in one of their subgroup analyses (Diabetes Care. 2015;38:1145-53). In that study with saxagliptin, among people older than 65 who received the study drug, the hazard ratio for major adverse cardiac events (MACE) was 0.92, compared with 1.15 for those younger than 65 (P value for interaction = .058). “So older people did great [on this drug],” Dr. Pratley said. “In fact, they had a bit of a decreased risk.” A similar association was seen in adults aged 75 years and older (HR, 1.01 in those younger than 75 years, vs. 0.95 in those aged 75 years and older; P value for interaction = .673). “This is telling us that saxagliptin is safe in the older population.”

In the EXAMINE trial, in which patients with type 2 diabetes who had had a recent acute coronary syndrome received either alogliptin or placebo, researchers conducted an analysis of patients older and younger than 65 (N Engl J Med. 2013;369:1327-35). They observed no significant interactions on the primary composite cardiovascular outcome in those younger than 65 (HR, 0.91) and those aged 65 and older (HR, 0.98).

Dr. Pratley noted that in cardiovascular outcome trials with sodium-glucose transporter 2 (SGLT2) inhibitors, the mean age of patients was 64, and 48%-50% of them were older than 65. In the EMPA-REG OUTCOME trial of empagliflozin, the hazard ratio for the primary cardiovascular outcome was 1.04 in patients younger than 65 and 0.71 in those aged 65 and older (P = .01; N Engl J Med, 2015;373:2117-28). “That was a significant interaction,” he said. In addition, the hazard ratio for cardiovascular death was 0.72 in those younger than 65, and 0.54 in those aged 65 and older (P = .21). “There was not a significant interaction here, but clearly there was some trending in the older patient population,” Dr. Pratley said.

In the LEADER study of liraglutide in patients with diabetes, the hazard ratio for the primary composite cardiovascular outcome was 0.87 in the overall population, 0.78 in patients younger than 60, and 0.90 in those aged 60 and older (P = 0.27; N Engl J Med. 2016;375:311-22). In a post hoc analysis that stratified LEADER patients into younger than 75 and 75 and older, the researchers observed a 31% reduction in the 75 and older population, compared with a 10% reduction in the younger population (P for interaction = .09; Ann Intern Med. 2019;170[6]:423-6). “This was driven largely by a decrease in nonfatal [myocardial infarction],” said Dr. Pratley, who was one of the study investigators. “But in patients who were 75 years and older, there was a 30% reduction in all-cause mortality in those treated with liraglutide, compared with 12% in those younger than 75 (P for interaction = .22). That interaction is not significant, but the theme here is that older populations do quite well.”

Based on such evidence, he said, DPP-4 and SGLT2 inhibitors and glucagon-like peptide–1 (GLP-1) receptor agonists can be safely used in older patients with cardiovascular disease or high risk. In particular, SGLT2 inhibitors and certain GLP-1 receptor agonists may be associated with an additional benefit in older individuals with cardiovascular disease, “perhaps because they’re the ones at highest risk,” Dr. Pratley said. “But we need further studies to better identify those older individuals who may be at highest risk of adverse cardiovascular complications from diabetes and who might benefit from targeted therapies.”

Many questions remain unanswered in efforts to provide optimal care to older adults with diabetes. “One of the problems is being inclusive in the older patient population,” Dr. Pratley said. “We tried to do a study of frail older individuals looking at different treatments and policies. It was difficult to recruit frail older individuals, even though they routinely are treated with the drugs we study in healthier populations. We need to know how to enroll patients, and which investigators are going to do these trials. Who is going to support these trials? Pharma? The NIH?”

Then there’s the question of what appropriate outcomes are in older individuals. “I think we can agree that hemoglobin A_1c is a surrogate of microvascular complications,” he said. “Do we need to be looking at outcomes like MACE, hospitalization for heart failure, death, progression of [chronic kidney disease], and perhaps cognitive function, physical function, sarcopenia, and quality of life?”

Dr. Pratley called for the development of a personalized approach to diabetes management that takes into account heterogeneity in disease pathogenesis, comorbidities, and patient preference.

“We need to change the focus to patient-important outcomes: dying, heart attack, strokes, and avoid therapeutic nihilism, which is still pervasive among many practitioners,” he said. “We also need to partner with primary care, because they take care of the majority of older individuals, and they need to understand how we’re evolving the goals of therapy. We need to educate them about the new guidelines and try to get them on board with some of the latest data that will help improve outcomes in our patients. We also need to understand the cost of diabetes and the cost effectiveness of interventions.”

He also recommends the development of a comprehensive evidence base for the use of drugs in older individuals. “I suggest pooled analyses within clinical development programs,” he said. “That’s been done for most development programs, but the phase 3 studies tend to enroll younger, healthier individuals. It would be good to do a meta-analysis across CVOTs [cardiovascular outcome trials] within different classes of medications.”

Dr. Pratley disclosed that all honoraria and fees he receives are directed to AdventHealth. These include serving on the advisory board or as consultant to AstraZeneca, GlaxoSmithKline, Glytec, Janssen, Ligand, Lilly, Merck, Mundipharma, Novo Nordisk, and Sanofi. He also has served as a speaker for AstraZeneca and Novo Nordisk, and has received research support from Lexicon, Ligand, Lilly, Merck, Novo Nordisk, and Sanofi. He receives no direct or indirect compensation.

[email protected]

LOS ANGELES – In the opinion of Richard Pratley, MD, it’s time for diabetes treatment guidelines to evolve in light of accumulating data from cardiovascular outcome trials in type 2 diabetes.

“They have evolved for the general patient population, and this should apply to older individuals as well,” Dr. Pratley said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “My fear is, there is therapeutic nihilism, the idea that by the time someone is 75 years old, the horse is out of the barn and you’re not going to be able to impact outcomes with directed therapy. I don’t think that’s true. Our current treatment guidelines for the treatment of diabetes in older individuals remain focused on glycemic control. It’s not hyperglycemia that’s killing people; it’s heart disease and renal disease.”

According to data from the United Nations, about 12% of the global population is older than 60. By 2050, that number is expected to reach 20%, which will continue to drive an epidemic of diabetes in the near future. Dr. Pratley, medical director of AdventHealth Diabetes Institute in Orlando, pointed out that diabetes in older individuals is not a homogeneous condition. “There are many people in my clinic who had type 1 diabetes diagnosed as kids, but I also have patients who have adult-onset type 1 diabetes,” he said. “We also have type 2 patients who can be diagnosed in their 20s, 30s, or 40s, and there are people who are diagnosed in their 70s and 80s. Now we are learning that there are different subtypes of diabetes; so even type 2 diabetes is not a homogeneous condition. There are people who are more insulin resistant or have more of an insulin secretory defect, and there’s a special type of older-onset type 2 diabetes. When you consider all this in talking about diabetes treatments, about 30% of patients in the United States are diagnosed [when they are] over the age of 60, so this is an ongoing issue.”

Older adults with diabetes may have longstanding diabetes with associated microvascular and macrovascular complications, he continued, or they may have newly diagnosed diabetes with evidence of end organ complications at the time of presentation. Or, they may have newly diagnosed diabetes without evidence of complications. “Does this matter? It does,” Dr. Pratley said. “The things we worry about with all patients with diabetes are the microvascular complications, but I would argue that the macrovascular complications, particularly diabetic nephropathy, are things we should have a laser focus on, because they have high morbidity and mortality, especially in older individuals.”

There are more than 28 cardiovascular outcomes trials in patients with type 2 diabetes ongoing or completed, and involving eight classes of medications, with more than 200,000 planned participants, Dr. Pratley said. Of those participants, 90,000 are older than 65 years, and 30,000 are older than 75 years. “This is great,” he said. “Not only do these cardiovascular outcome studies give us a lot of information about the safety and efficacy of these drugs in the general population, we can now dig in to this specific patient population.” For example, in cardiovascular outcomes trials with dipeptidyl peptidase–4 (DPP-4) inhibitors, the mean age of patients was 65. About half of the patients were older than 65, and 10%-14% were older than 75.

Investigators in the SAVOR-TIMI 53 trial examined age in one of their subgroup analyses (Diabetes Care. 2015;38:1145-53). In that study with saxagliptin, among people older than 65 who received the study drug, the hazard ratio for major adverse cardiac events (MACE) was 0.92, compared with 1.15 for those younger than 65 (P value for interaction = .058). “So older people did great [on this drug],” Dr. Pratley said. “In fact, they had a bit of a decreased risk.” A similar association was seen in adults aged 75 years and older (HR, 1.01 in those younger than 75 years, vs. 0.95 in those aged 75 years and older; P value for interaction = .673). “This is telling us that saxagliptin is safe in the older population.”

In the EXAMINE trial, in which patients with type 2 diabetes who had had a recent acute coronary syndrome received either alogliptin or placebo, researchers conducted an analysis of patients older and younger than 65 (N Engl J Med. 2013;369:1327-35). They observed no significant interactions on the primary composite cardiovascular outcome in those younger than 65 (HR, 0.91) and those aged 65 and older (HR, 0.98).

Dr. Pratley noted that in cardiovascular outcome trials with sodium-glucose transporter 2 (SGLT2) inhibitors, the mean age of patients was 64, and 48%-50% of them were older than 65. In the EMPA-REG OUTCOME trial of empagliflozin, the hazard ratio for the primary cardiovascular outcome was 1.04 in patients younger than 65 and 0.71 in those aged 65 and older (P = .01; N Engl J Med, 2015;373:2117-28). “That was a significant interaction,” he said. In addition, the hazard ratio for cardiovascular death was 0.72 in those younger than 65, and 0.54 in those aged 65 and older (P = .21). “There was not a significant interaction here, but clearly there was some trending in the older patient population,” Dr. Pratley said.

In the LEADER study of liraglutide in patients with diabetes, the hazard ratio for the primary composite cardiovascular outcome was 0.87 in the overall population, 0.78 in patients younger than 60, and 0.90 in those aged 60 and older (P = 0.27; N Engl J Med. 2016;375:311-22). In a post hoc analysis that stratified LEADER patients into younger than 75 and 75 and older, the researchers observed a 31% reduction in the 75 and older population, compared with a 10% reduction in the younger population (P for interaction = .09; Ann Intern Med. 2019;170[6]:423-6). “This was driven largely by a decrease in nonfatal [myocardial infarction],” said Dr. Pratley, who was one of the study investigators. “But in patients who were 75 years and older, there was a 30% reduction in all-cause mortality in those treated with liraglutide, compared with 12% in those younger than 75 (P for interaction = .22). That interaction is not significant, but the theme here is that older populations do quite well.”

Based on such evidence, he said, DPP-4 and SGLT2 inhibitors and glucagon-like peptide–1 (GLP-1) receptor agonists can be safely used in older patients with cardiovascular disease or high risk. In particular, SGLT2 inhibitors and certain GLP-1 receptor agonists may be associated with an additional benefit in older individuals with cardiovascular disease, “perhaps because they’re the ones at highest risk,” Dr. Pratley said. “But we need further studies to better identify those older individuals who may be at highest risk of adverse cardiovascular complications from diabetes and who might benefit from targeted therapies.”

Many questions remain unanswered in efforts to provide optimal care to older adults with diabetes. “One of the problems is being inclusive in the older patient population,” Dr. Pratley said. “We tried to do a study of frail older individuals looking at different treatments and policies. It was difficult to recruit frail older individuals, even though they routinely are treated with the drugs we study in healthier populations. We need to know how to enroll patients, and which investigators are going to do these trials. Who is going to support these trials? Pharma? The NIH?”

Then there’s the question of what appropriate outcomes are in older individuals. “I think we can agree that hemoglobin A_1c is a surrogate of microvascular complications,” he said. “Do we need to be looking at outcomes like MACE, hospitalization for heart failure, death, progression of [chronic kidney disease], and perhaps cognitive function, physical function, sarcopenia, and quality of life?”

Dr. Pratley called for the development of a personalized approach to diabetes management that takes into account heterogeneity in disease pathogenesis, comorbidities, and patient preference.

“We need to change the focus to patient-important outcomes: dying, heart attack, strokes, and avoid therapeutic nihilism, which is still pervasive among many practitioners,” he said. “We also need to partner with primary care, because they take care of the majority of older individuals, and they need to understand how we’re evolving the goals of therapy. We need to educate them about the new guidelines and try to get them on board with some of the latest data that will help improve outcomes in our patients. We also need to understand the cost of diabetes and the cost effectiveness of interventions.”

He also recommends the development of a comprehensive evidence base for the use of drugs in older individuals. “I suggest pooled analyses within clinical development programs,” he said. “That’s been done for most development programs, but the phase 3 studies tend to enroll younger, healthier individuals. It would be good to do a meta-analysis across CVOTs [cardiovascular outcome trials] within different classes of medications.”

Dr. Pratley disclosed that all honoraria and fees he receives are directed to AdventHealth. These include serving on the advisory board or as consultant to AstraZeneca, GlaxoSmithKline, Glytec, Janssen, Ligand, Lilly, Merck, Mundipharma, Novo Nordisk, and Sanofi. He also has served as a speaker for AstraZeneca and Novo Nordisk, and has received research support from Lexicon, Ligand, Lilly, Merck, Novo Nordisk, and Sanofi. He receives no direct or indirect compensation.

[email protected]

LOS ANGELES – In the opinion of Richard Pratley, MD, it’s time for diabetes treatment guidelines to evolve in light of accumulating data from cardiovascular outcome trials in type 2 diabetes.

“They have evolved for the general patient population, and this should apply to older individuals as well,” Dr. Pratley said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “My fear is, there is therapeutic nihilism, the idea that by the time someone is 75 years old, the horse is out of the barn and you’re not going to be able to impact outcomes with directed therapy. I don’t think that’s true. Our current treatment guidelines for the treatment of diabetes in older individuals remain focused on glycemic control. It’s not hyperglycemia that’s killing people; it’s heart disease and renal disease.”

According to data from the United Nations, about 12% of the global population is older than 60. By 2050, that number is expected to reach 20%, which will continue to drive an epidemic of diabetes in the near future. Dr. Pratley, medical director of AdventHealth Diabetes Institute in Orlando, pointed out that diabetes in older individuals is not a homogeneous condition. “There are many people in my clinic who had type 1 diabetes diagnosed as kids, but I also have patients who have adult-onset type 1 diabetes,” he said. “We also have type 2 patients who can be diagnosed in their 20s, 30s, or 40s, and there are people who are diagnosed in their 70s and 80s. Now we are learning that there are different subtypes of diabetes; so even type 2 diabetes is not a homogeneous condition. There are people who are more insulin resistant or have more of an insulin secretory defect, and there’s a special type of older-onset type 2 diabetes. When you consider all this in talking about diabetes treatments, about 30% of patients in the United States are diagnosed [when they are] over the age of 60, so this is an ongoing issue.”

Older adults with diabetes may have longstanding diabetes with associated microvascular and macrovascular complications, he continued, or they may have newly diagnosed diabetes with evidence of end organ complications at the time of presentation. Or, they may have newly diagnosed diabetes without evidence of complications. “Does this matter? It does,” Dr. Pratley said. “The things we worry about with all patients with diabetes are the microvascular complications, but I would argue that the macrovascular complications, particularly diabetic nephropathy, are things we should have a laser focus on, because they have high morbidity and mortality, especially in older individuals.”

There are more than 28 cardiovascular outcomes trials in patients with type 2 diabetes ongoing or completed, and involving eight classes of medications, with more than 200,000 planned participants, Dr. Pratley said. Of those participants, 90,000 are older than 65 years, and 30,000 are older than 75 years. “This is great,” he said. “Not only do these cardiovascular outcome studies give us a lot of information about the safety and efficacy of these drugs in the general population, we can now dig in to this specific patient population.” For example, in cardiovascular outcomes trials with dipeptidyl peptidase–4 (DPP-4) inhibitors, the mean age of patients was 65. About half of the patients were older than 65, and 10%-14% were older than 75.

Investigators in the SAVOR-TIMI 53 trial examined age in one of their subgroup analyses (Diabetes Care. 2015;38:1145-53). In that study with saxagliptin, among people older than 65 who received the study drug, the hazard ratio for major adverse cardiac events (MACE) was 0.92, compared with 1.15 for those younger than 65 (P value for interaction = .058). “So older people did great [on this drug],” Dr. Pratley said. “In fact, they had a bit of a decreased risk.” A similar association was seen in adults aged 75 years and older (HR, 1.01 in those younger than 75 years, vs. 0.95 in those aged 75 years and older; P value for interaction = .673). “This is telling us that saxagliptin is safe in the older population.”

In the EXAMINE trial, in which patients with type 2 diabetes who had had a recent acute coronary syndrome received either alogliptin or placebo, researchers conducted an analysis of patients older and younger than 65 (N Engl J Med. 2013;369:1327-35). They observed no significant interactions on the primary composite cardiovascular outcome in those younger than 65 (HR, 0.91) and those aged 65 and older (HR, 0.98).

Dr. Pratley noted that in cardiovascular outcome trials with sodium-glucose transporter 2 (SGLT2) inhibitors, the mean age of patients was 64, and 48%-50% of them were older than 65. In the EMPA-REG OUTCOME trial of empagliflozin, the hazard ratio for the primary cardiovascular outcome was 1.04 in patients younger than 65 and 0.71 in those aged 65 and older (P = .01; N Engl J Med, 2015;373:2117-28). “That was a significant interaction,” he said. In addition, the hazard ratio for cardiovascular death was 0.72 in those younger than 65, and 0.54 in those aged 65 and older (P = .21). “There was not a significant interaction here, but clearly there was some trending in the older patient population,” Dr. Pratley said.

In the LEADER study of liraglutide in patients with diabetes, the hazard ratio for the primary composite cardiovascular outcome was 0.87 in the overall population, 0.78 in patients younger than 60, and 0.90 in those aged 60 and older (P = 0.27; N Engl J Med. 2016;375:311-22). In a post hoc analysis that stratified LEADER patients into younger than 75 and 75 and older, the researchers observed a 31% reduction in the 75 and older population, compared with a 10% reduction in the younger population (P for interaction = .09; Ann Intern Med. 2019;170[6]:423-6). “This was driven largely by a decrease in nonfatal [myocardial infarction],” said Dr. Pratley, who was one of the study investigators. “But in patients who were 75 years and older, there was a 30% reduction in all-cause mortality in those treated with liraglutide, compared with 12% in those younger than 75 (P for interaction = .22). That interaction is not significant, but the theme here is that older populations do quite well.”

Based on such evidence, he said, DPP-4 and SGLT2 inhibitors and glucagon-like peptide–1 (GLP-1) receptor agonists can be safely used in older patients with cardiovascular disease or high risk. In particular, SGLT2 inhibitors and certain GLP-1 receptor agonists may be associated with an additional benefit in older individuals with cardiovascular disease, “perhaps because they’re the ones at highest risk,” Dr. Pratley said. “But we need further studies to better identify those older individuals who may be at highest risk of adverse cardiovascular complications from diabetes and who might benefit from targeted therapies.”

Many questions remain unanswered in efforts to provide optimal care to older adults with diabetes. “One of the problems is being inclusive in the older patient population,” Dr. Pratley said. “We tried to do a study of frail older individuals looking at different treatments and policies. It was difficult to recruit frail older individuals, even though they routinely are treated with the drugs we study in healthier populations. We need to know how to enroll patients, and which investigators are going to do these trials. Who is going to support these trials? Pharma? The NIH?”

Then there’s the question of what appropriate outcomes are in older individuals. “I think we can agree that hemoglobin A_1c is a surrogate of microvascular complications,” he said. “Do we need to be looking at outcomes like MACE, hospitalization for heart failure, death, progression of [chronic kidney disease], and perhaps cognitive function, physical function, sarcopenia, and quality of life?”

Dr. Pratley called for the development of a personalized approach to diabetes management that takes into account heterogeneity in disease pathogenesis, comorbidities, and patient preference.

“We need to change the focus to patient-important outcomes: dying, heart attack, strokes, and avoid therapeutic nihilism, which is still pervasive among many practitioners,” he said. “We also need to partner with primary care, because they take care of the majority of older individuals, and they need to understand how we’re evolving the goals of therapy. We need to educate them about the new guidelines and try to get them on board with some of the latest data that will help improve outcomes in our patients. We also need to understand the cost of diabetes and the cost effectiveness of interventions.”

He also recommends the development of a comprehensive evidence base for the use of drugs in older individuals. “I suggest pooled analyses within clinical development programs,” he said. “That’s been done for most development programs, but the phase 3 studies tend to enroll younger, healthier individuals. It would be good to do a meta-analysis across CVOTs [cardiovascular outcome trials] within different classes of medications.”

Dr. Pratley disclosed that all honoraria and fees he receives are directed to AdventHealth. These include serving on the advisory board or as consultant to AstraZeneca, GlaxoSmithKline, Glytec, Janssen, Ligand, Lilly, Merck, Mundipharma, Novo Nordisk, and Sanofi. He also has served as a speaker for AstraZeneca and Novo Nordisk, and has received research support from Lexicon, Ligand, Lilly, Merck, Novo Nordisk, and Sanofi. He receives no direct or indirect compensation.

[email protected]

The Food and Drug Administration has granted accelerated approval to Vyondys 53 (golodirsen) to treat patients with Duchenne muscular dystrophy (DMD) who have a mutation of the dystrophin gene that is amenable to exon 53 skipping. About 8% of patients with DMD have this type of mutation. Further research is required to establish whether the antisense oligonucleotide provides clinical benefit, the agency said.

Separately, the agency approved the first newborn screening test for DMD.

DMD is a “rare and devastating disease,” said Billy Dunn, MD, acting director of the office of neuroscience in the FDA’s Center for Drug Evaluation and Research.

“Patients ... who have a confirmed mutation of the dystrophin gene amenable to exon 53 skipping will now have available the first treatment targeted specifically for this disease subtype,” Dr. Dunn said in a news release. “Use of the accelerated approval pathway will make Vyondys 53 available to patients based on initial data, and we look forward to learning more about the drug’s clinical benefit from the ongoing confirmatory clinical trial.”
 

A surrogate endpoint

The FDA approved Vyondys 53 based on the surrogate endpoint of increased dystrophin production in the skeletal muscle in some patients treated with the drug. Sarepta Therapeutics, the developer of Vyondys 53, evaluated the treatment in a two-part clinical study. In the first part, eight patients with DMD received Vyondys 53, and four received placebo. In the second part, 25 patients, including the 12 patients from the first part, received open-label treatment. Dystrophin levels increased from 0.10% of normal at baseline to 1.02% of normal after at least 48 weeks of treatment.

A placebo-controlled, confirmatory trial is expected to conclude by 2024, the company said. If the trial does not confirm clinical benefit, the FDA could withdraw approval of the drug.

The most common side effects in patients who received Vyondys 53 include headache, fever, fall, cough, vomiting, abdominal pain, cold symptoms, and nausea. Some patients had hypersensitivity reactions. Renal toxicity occurred in animal studies of golodirsen, but not in the clinical studies. Renal toxicity, however, has occurred after treatment with other antisense oligonucleotides, the FDA noted.

Sarepta said Vyondys 53, an injection, would be available immediately. The drug is the company’s second RNA exon-skipping treatment for DMD. The FDA approved the first treatment, Exondys 51 (eteplirsen), in 2016. Together, the two drugs can treat about 20% of patients with DMD, the company said.
 

Newborn screening

On the same day, Dec. 12, 2019, the FDA authorized marketing of the first test to aid in newborn screening for DMD. Although authorization for the GSP Neonatal Creatine Kinase–MM kit enables laboratories to add this test to their newborn screening panel, it “does not signal a recommendation for DMD to be added ... as a condition for which newborn screening is recommended,” the agency said. In addition, the FDA noted that the kit is not meant to diagnose DMD or to screen for other muscular dystrophies.

The GSP Neonatal Creatine Kinase–MM kit measures the concentration of CK-MM, a type of protein that increases when there is muscle damage. The test measures CK-MM in dried blood samples collected from a newborn’s heel 24-48 hours after birth. Elevated levels may indicate DMD, but physicians must confirm the diagnosis using other methods, such as muscle biopsies, genetic testing, and other laboratory tests.

DMD primarily affects boys, and patients often do not have a family history of the condition. About 1 in 3,600 male live-born infants worldwide have DMD. Symptom onset usually occurs between the ages of 3 and 5 years.

The FDA reviewed the kit through the de novo premarket review pathway for low to moderate risk devices. In a clinical study of 3,041 newborns, the kit identified the four screened newborns who had DMD-causing genetic mutations. In addition, the test correctly identified 30 samples from newborns with clinically confirmed cases of DMD.

PerkinElmer developed the GSP Neonatal Creatine Kinase–MM kit.
 

[email protected]

The Food and Drug Administration has granted accelerated approval to Vyondys 53 (golodirsen) to treat patients with Duchenne muscular dystrophy (DMD) who have a mutation of the dystrophin gene that is amenable to exon 53 skipping. About 8% of patients with DMD have this type of mutation. Further research is required to establish whether the antisense oligonucleotide provides clinical benefit, the agency said.

Separately, the agency approved the first newborn screening test for DMD.

DMD is a “rare and devastating disease,” said Billy Dunn, MD, acting director of the office of neuroscience in the FDA’s Center for Drug Evaluation and Research.

“Patients ... who have a confirmed mutation of the dystrophin gene amenable to exon 53 skipping will now have available the first treatment targeted specifically for this disease subtype,” Dr. Dunn said in a news release. “Use of the accelerated approval pathway will make Vyondys 53 available to patients based on initial data, and we look forward to learning more about the drug’s clinical benefit from the ongoing confirmatory clinical trial.”
 

A surrogate endpoint

The FDA approved Vyondys 53 based on the surrogate endpoint of increased dystrophin production in the skeletal muscle in some patients treated with the drug. Sarepta Therapeutics, the developer of Vyondys 53, evaluated the treatment in a two-part clinical study. In the first part, eight patients with DMD received Vyondys 53, and four received placebo. In the second part, 25 patients, including the 12 patients from the first part, received open-label treatment. Dystrophin levels increased from 0.10% of normal at baseline to 1.02% of normal after at least 48 weeks of treatment.

A placebo-controlled, confirmatory trial is expected to conclude by 2024, the company said. If the trial does not confirm clinical benefit, the FDA could withdraw approval of the drug.

The most common side effects in patients who received Vyondys 53 include headache, fever, fall, cough, vomiting, abdominal pain, cold symptoms, and nausea. Some patients had hypersensitivity reactions. Renal toxicity occurred in animal studies of golodirsen, but not in the clinical studies. Renal toxicity, however, has occurred after treatment with other antisense oligonucleotides, the FDA noted.

Sarepta said Vyondys 53, an injection, would be available immediately. The drug is the company’s second RNA exon-skipping treatment for DMD. The FDA approved the first treatment, Exondys 51 (eteplirsen), in 2016. Together, the two drugs can treat about 20% of patients with DMD, the company said.
 

Newborn screening

On the same day, Dec. 12, 2019, the FDA authorized marketing of the first test to aid in newborn screening for DMD. Although authorization for the GSP Neonatal Creatine Kinase–MM kit enables laboratories to add this test to their newborn screening panel, it “does not signal a recommendation for DMD to be added ... as a condition for which newborn screening is recommended,” the agency said. In addition, the FDA noted that the kit is not meant to diagnose DMD or to screen for other muscular dystrophies.

The GSP Neonatal Creatine Kinase–MM kit measures the concentration of CK-MM, a type of protein that increases when there is muscle damage. The test measures CK-MM in dried blood samples collected from a newborn’s heel 24-48 hours after birth. Elevated levels may indicate DMD, but physicians must confirm the diagnosis using other methods, such as muscle biopsies, genetic testing, and other laboratory tests.

DMD primarily affects boys, and patients often do not have a family history of the condition. About 1 in 3,600 male live-born infants worldwide have DMD. Symptom onset usually occurs between the ages of 3 and 5 years.

The FDA reviewed the kit through the de novo premarket review pathway for low to moderate risk devices. In a clinical study of 3,041 newborns, the kit identified the four screened newborns who had DMD-causing genetic mutations. In addition, the test correctly identified 30 samples from newborns with clinically confirmed cases of DMD.

PerkinElmer developed the GSP Neonatal Creatine Kinase–MM kit.
 

[email protected]

The Food and Drug Administration has granted accelerated approval to Vyondys 53 (golodirsen) to treat patients with Duchenne muscular dystrophy (DMD) who have a mutation of the dystrophin gene that is amenable to exon 53 skipping. About 8% of patients with DMD have this type of mutation. Further research is required to establish whether the antisense oligonucleotide provides clinical benefit, the agency said.

Separately, the agency approved the first newborn screening test for DMD.

DMD is a “rare and devastating disease,” said Billy Dunn, MD, acting director of the office of neuroscience in the FDA’s Center for Drug Evaluation and Research.

“Patients ... who have a confirmed mutation of the dystrophin gene amenable to exon 53 skipping will now have available the first treatment targeted specifically for this disease subtype,” Dr. Dunn said in a news release. “Use of the accelerated approval pathway will make Vyondys 53 available to patients based on initial data, and we look forward to learning more about the drug’s clinical benefit from the ongoing confirmatory clinical trial.”
 

A surrogate endpoint

The FDA approved Vyondys 53 based on the surrogate endpoint of increased dystrophin production in the skeletal muscle in some patients treated with the drug. Sarepta Therapeutics, the developer of Vyondys 53, evaluated the treatment in a two-part clinical study. In the first part, eight patients with DMD received Vyondys 53, and four received placebo. In the second part, 25 patients, including the 12 patients from the first part, received open-label treatment. Dystrophin levels increased from 0.10% of normal at baseline to 1.02% of normal after at least 48 weeks of treatment.

A placebo-controlled, confirmatory trial is expected to conclude by 2024, the company said. If the trial does not confirm clinical benefit, the FDA could withdraw approval of the drug.

The most common side effects in patients who received Vyondys 53 include headache, fever, fall, cough, vomiting, abdominal pain, cold symptoms, and nausea. Some patients had hypersensitivity reactions. Renal toxicity occurred in animal studies of golodirsen, but not in the clinical studies. Renal toxicity, however, has occurred after treatment with other antisense oligonucleotides, the FDA noted.

Sarepta said Vyondys 53, an injection, would be available immediately. The drug is the company’s second RNA exon-skipping treatment for DMD. The FDA approved the first treatment, Exondys 51 (eteplirsen), in 2016. Together, the two drugs can treat about 20% of patients with DMD, the company said.
 

Newborn screening

On the same day, Dec. 12, 2019, the FDA authorized marketing of the first test to aid in newborn screening for DMD. Although authorization for the GSP Neonatal Creatine Kinase–MM kit enables laboratories to add this test to their newborn screening panel, it “does not signal a recommendation for DMD to be added ... as a condition for which newborn screening is recommended,” the agency said. In addition, the FDA noted that the kit is not meant to diagnose DMD or to screen for other muscular dystrophies.

The GSP Neonatal Creatine Kinase–MM kit measures the concentration of CK-MM, a type of protein that increases when there is muscle damage. The test measures CK-MM in dried blood samples collected from a newborn’s heel 24-48 hours after birth. Elevated levels may indicate DMD, but physicians must confirm the diagnosis using other methods, such as muscle biopsies, genetic testing, and other laboratory tests.

DMD primarily affects boys, and patients often do not have a family history of the condition. About 1 in 3,600 male live-born infants worldwide have DMD. Symptom onset usually occurs between the ages of 3 and 5 years.

The FDA reviewed the kit through the de novo premarket review pathway for low to moderate risk devices. In a clinical study of 3,041 newborns, the kit identified the four screened newborns who had DMD-causing genetic mutations. In addition, the test correctly identified 30 samples from newborns with clinically confirmed cases of DMD.

PerkinElmer developed the GSP Neonatal Creatine Kinase–MM kit.
 

[email protected]

LOS ANGELES – Patients with diabetes had significantly higher adjusted risk of bleeding, cardiovascular-related death, and poorer net outcomes, particularly those treated with insulin, a subanalysis of the ENGAGE AF-TIMI 48 trial has shown.

Doug Brunk/MDedge News

In addition, the pharmacokinetic and pharmacodynamic profile of the study drug, edoxaban – a novel oral anticoagulant drug and a direct factor Xa inhibitor – was generally similar in patients with and without diabetes.

“We know that atrial fibrillation is associated with a fivefold increased risk of stroke,” Anna Plitt, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “Type 2 diabetes is associated with a twofold increased risk of stroke, and longer duration of diabetes is associated with even higher ischemic event rates. The coexistence of [atrial fibrillation] and type 2 diabetes further increases thromboembolic risk.”

Dr. Plitt, a cardiology fellow at Mount Sinai Hospital, New York, noted that, although type 2 diabetes is characterized by a prothrombotic and inflammatory state, the mechanism of action by which hyperglycemia and/or insulin resistance leads to the development of atrial fibrillation (AFib) remains unknown. “Given the complex clinical interactions between AFib and type 2 diabetes, care for these patients remains challenging,” she said. “Recommendations for anticoagulation managements vary based on the presence of additional risk factors and which guidelines are followed.”

In the ENGAGE AF-TIMI 48 trial, 21,105 patients with documented AFib within the previous 12 months were randomized to standard-care warfarin or high-dose edoxaban (60 mg daily) or low-dose edoxaban (30 mg daily). The edoxaban dose was reduced by 50% if creatinine clearance reached 30-50 mL/min, patient weight reached 60 kg or less, or there was concomitant use of a P-glycoprotein inhibitor (N Engl J Med. 2013;369:2093-104). The median follow-up was 2.8 years, and the primary efficacy endpoint was stroke or systemic embolic events (SEEs). The primary safety endpoint was major bleeding, as defined by the International Society on Thrombosis and Haemostasis criteria.

The findings showed that edoxaban was noninferior to warfarin in preventing stroke/SEEs. It also significantly reduced major bleeding, cardiovascular death, and net outcomes. “Therefore, the higher dose of edoxaban was approved globally for treating patients with AFib,” Dr. Plitt said. “The lower-dose regimen was not approved because there was less protection from ischemic stroke, compared with warfarin.”

For the current subanalysis, Dr. Plitt and colleagues set out to further evaluate outcomes of patients enrolled in the ENGAGE AF-TIMI 48 trial, excluding those who were in the low-dose edoxaban group. The presence or absence of diabetes was determined by the local investigator at randomization. The investigators further stratified patients into insulin-treated and non–insulin treated groups and used multivariate Cox regression models to adjust for baseline characteristics across the groups stratified by diabetes status. Next, they analyzed edoxaban concentration, anti–factor Xa activity, and international normalized ratio data and compared outcomes of high-dose edoxaban with those of warfarin.

The primary endpoint and the primary safety endpoint of interest were the same as in the main ENGAGE AF-TIMI 48 trial. Key secondary endpoints included in the subanalysis were cardiovascular death, stroke/SEE, major adverse cardiovascular events (MACE, a composite of myocardial infarction, stroke, SEE, or death because of cardiovascular cause or bleeding), and all-cause death.

In all, 7,624 of the 21,105 patients in the ENGAGE AF-TIMI 48 trial had diabetes, for a rate of 36%. Most of the patients with diabetes did not require insulin (30%), while 6% did. There were fewer female patients with diabetes than without (37% vs. 39%, respectively). Of note was that history of prior stroke/transient ischemic attack was higher in the no-diabetes group than in the diabetes group (33% vs. 21%), as was congestive heart failure (63% vs. 48%).

The mean CHA2DS2-VASc score for predicting thromboembolic risk (0, low risk; greater than 1, high risk) was 4.6 in the diabetes group and 4.2 in the no-diabetes group. When diabetes was not included in the score, the mean CHA2DS2-VASc score was 3.6 in the diabetes group. “Because the trial entry criteria required a minimum CHADS2 score of 2, patients without diabetes were enriched with stroke risk factors other than diabetes,” Dr. Plitt said.

Adjusted outcomes from the subanalysis showed that the risk of stroke/SEE was similar between patients with and without diabetes (hazard ratio, 1.08). However, patients with diabetes were at higher adjusted risk for cardiovascular death than patients without diabetes (HR, 1.29), MACE (HR, 1.28), major bleed (HR, 1.28), and the net outcome of stroke, SEE, major bleed, or all-cause death (HR, 1.25).

The researchers also analyzed the pharmacodynamic and pharmacokinetic data of high-dose edoxaban, stratified by diabetes status. They found that the parameters were generally similar between patients with and without diabetes, including trough concentrations of edoxaban (34.3 and 37.2 ng/mL, respectively; P = .04), trough exogenous anti–factor Xa activity (0.59 and 0.68 IU/mL; P = .11), and the percentage change from baseline in the peak endogenous anti–factor Xa activity (P = .66). The percentage changes from baseline of the trough endogenous anti–factor Xa activity was slightly lower in patients with diabetes, compared with patients without diabetes (P less than .001). “However, these modest differences between the two groups are of unclear clinical significance,” Dr. Plitt said.

Results from the main ENGAGE AF-TIMI 48 showed that the rates of stroke/SEE were reduced by 13% on high-dose edoxaban. However, the subanalysis found no significant effect modification in the reduction in stroke/SEE with edoxaban, compared with warfarin, when stratified by diabetes status (reductions of 16% vs. 7% in the no-diabetes and diabetes groups, respectively; P for interaction = .54). The researchers also observed similar reductions with edoxaban in the risks of secondary outcomes when patients were stratified by diabetes status.

In another finding, patients with diabetes who were treated with insulin were at a higher adjusted risk for all outcomes, compared with those with diabetes who were not treated with insulin. This included stroke/SEE (HR, 1.44), cardiovascular-related death (HR, 1.83), MACE (HR, 1.78), major bleed (HR, 1.31), and net outcome (HR, 1.57).

Next, the researchers compared the study endpoints of high-dose edoxaban and warfarin, with and without insulin. “None of the efficacy, safety, or net outcomes demonstrated evidence of treatment effect modification related to the use of insulin among [patients with diabetes],” she said.

Dr. Plitt disclosed having received honoraria for educational activities from Bristol-Myers Squibb.

[email protected]

LOS ANGELES – Patients with diabetes had significantly higher adjusted risk of bleeding, cardiovascular-related death, and poorer net outcomes, particularly those treated with insulin, a subanalysis of the ENGAGE AF-TIMI 48 trial has shown.

Doug Brunk/MDedge News

In addition, the pharmacokinetic and pharmacodynamic profile of the study drug, edoxaban – a novel oral anticoagulant drug and a direct factor Xa inhibitor – was generally similar in patients with and without diabetes.

“We know that atrial fibrillation is associated with a fivefold increased risk of stroke,” Anna Plitt, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “Type 2 diabetes is associated with a twofold increased risk of stroke, and longer duration of diabetes is associated with even higher ischemic event rates. The coexistence of [atrial fibrillation] and type 2 diabetes further increases thromboembolic risk.”

Dr. Plitt, a cardiology fellow at Mount Sinai Hospital, New York, noted that, although type 2 diabetes is characterized by a prothrombotic and inflammatory state, the mechanism of action by which hyperglycemia and/or insulin resistance leads to the development of atrial fibrillation (AFib) remains unknown. “Given the complex clinical interactions between AFib and type 2 diabetes, care for these patients remains challenging,” she said. “Recommendations for anticoagulation managements vary based on the presence of additional risk factors and which guidelines are followed.”

In the ENGAGE AF-TIMI 48 trial, 21,105 patients with documented AFib within the previous 12 months were randomized to standard-care warfarin or high-dose edoxaban (60 mg daily) or low-dose edoxaban (30 mg daily). The edoxaban dose was reduced by 50% if creatinine clearance reached 30-50 mL/min, patient weight reached 60 kg or less, or there was concomitant use of a P-glycoprotein inhibitor (N Engl J Med. 2013;369:2093-104). The median follow-up was 2.8 years, and the primary efficacy endpoint was stroke or systemic embolic events (SEEs). The primary safety endpoint was major bleeding, as defined by the International Society on Thrombosis and Haemostasis criteria.

The findings showed that edoxaban was noninferior to warfarin in preventing stroke/SEEs. It also significantly reduced major bleeding, cardiovascular death, and net outcomes. “Therefore, the higher dose of edoxaban was approved globally for treating patients with AFib,” Dr. Plitt said. “The lower-dose regimen was not approved because there was less protection from ischemic stroke, compared with warfarin.”

For the current subanalysis, Dr. Plitt and colleagues set out to further evaluate outcomes of patients enrolled in the ENGAGE AF-TIMI 48 trial, excluding those who were in the low-dose edoxaban group. The presence or absence of diabetes was determined by the local investigator at randomization. The investigators further stratified patients into insulin-treated and non–insulin treated groups and used multivariate Cox regression models to adjust for baseline characteristics across the groups stratified by diabetes status. Next, they analyzed edoxaban concentration, anti–factor Xa activity, and international normalized ratio data and compared outcomes of high-dose edoxaban with those of warfarin.

The primary endpoint and the primary safety endpoint of interest were the same as in the main ENGAGE AF-TIMI 48 trial. Key secondary endpoints included in the subanalysis were cardiovascular death, stroke/SEE, major adverse cardiovascular events (MACE, a composite of myocardial infarction, stroke, SEE, or death because of cardiovascular cause or bleeding), and all-cause death.

In all, 7,624 of the 21,105 patients in the ENGAGE AF-TIMI 48 trial had diabetes, for a rate of 36%. Most of the patients with diabetes did not require insulin (30%), while 6% did. There were fewer female patients with diabetes than without (37% vs. 39%, respectively). Of note was that history of prior stroke/transient ischemic attack was higher in the no-diabetes group than in the diabetes group (33% vs. 21%), as was congestive heart failure (63% vs. 48%).

The mean CHA2DS2-VASc score for predicting thromboembolic risk (0, low risk; greater than 1, high risk) was 4.6 in the diabetes group and 4.2 in the no-diabetes group. When diabetes was not included in the score, the mean CHA2DS2-VASc score was 3.6 in the diabetes group. “Because the trial entry criteria required a minimum CHADS2 score of 2, patients without diabetes were enriched with stroke risk factors other than diabetes,” Dr. Plitt said.

Adjusted outcomes from the subanalysis showed that the risk of stroke/SEE was similar between patients with and without diabetes (hazard ratio, 1.08). However, patients with diabetes were at higher adjusted risk for cardiovascular death than patients without diabetes (HR, 1.29), MACE (HR, 1.28), major bleed (HR, 1.28), and the net outcome of stroke, SEE, major bleed, or all-cause death (HR, 1.25).

The researchers also analyzed the pharmacodynamic and pharmacokinetic data of high-dose edoxaban, stratified by diabetes status. They found that the parameters were generally similar between patients with and without diabetes, including trough concentrations of edoxaban (34.3 and 37.2 ng/mL, respectively; P = .04), trough exogenous anti–factor Xa activity (0.59 and 0.68 IU/mL; P = .11), and the percentage change from baseline in the peak endogenous anti–factor Xa activity (P = .66). The percentage changes from baseline of the trough endogenous anti–factor Xa activity was slightly lower in patients with diabetes, compared with patients without diabetes (P less than .001). “However, these modest differences between the two groups are of unclear clinical significance,” Dr. Plitt said.

Results from the main ENGAGE AF-TIMI 48 showed that the rates of stroke/SEE were reduced by 13% on high-dose edoxaban. However, the subanalysis found no significant effect modification in the reduction in stroke/SEE with edoxaban, compared with warfarin, when stratified by diabetes status (reductions of 16% vs. 7% in the no-diabetes and diabetes groups, respectively; P for interaction = .54). The researchers also observed similar reductions with edoxaban in the risks of secondary outcomes when patients were stratified by diabetes status.

In another finding, patients with diabetes who were treated with insulin were at a higher adjusted risk for all outcomes, compared with those with diabetes who were not treated with insulin. This included stroke/SEE (HR, 1.44), cardiovascular-related death (HR, 1.83), MACE (HR, 1.78), major bleed (HR, 1.31), and net outcome (HR, 1.57).

Next, the researchers compared the study endpoints of high-dose edoxaban and warfarin, with and without insulin. “None of the efficacy, safety, or net outcomes demonstrated evidence of treatment effect modification related to the use of insulin among [patients with diabetes],” she said.

Dr. Plitt disclosed having received honoraria for educational activities from Bristol-Myers Squibb.

[email protected]

LOS ANGELES – Patients with diabetes had significantly higher adjusted risk of bleeding, cardiovascular-related death, and poorer net outcomes, particularly those treated with insulin, a subanalysis of the ENGAGE AF-TIMI 48 trial has shown.

Doug Brunk/MDedge News

In addition, the pharmacokinetic and pharmacodynamic profile of the study drug, edoxaban – a novel oral anticoagulant drug and a direct factor Xa inhibitor – was generally similar in patients with and without diabetes.

“We know that atrial fibrillation is associated with a fivefold increased risk of stroke,” Anna Plitt, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “Type 2 diabetes is associated with a twofold increased risk of stroke, and longer duration of diabetes is associated with even higher ischemic event rates. The coexistence of [atrial fibrillation] and type 2 diabetes further increases thromboembolic risk.”

Dr. Plitt, a cardiology fellow at Mount Sinai Hospital, New York, noted that, although type 2 diabetes is characterized by a prothrombotic and inflammatory state, the mechanism of action by which hyperglycemia and/or insulin resistance leads to the development of atrial fibrillation (AFib) remains unknown. “Given the complex clinical interactions between AFib and type 2 diabetes, care for these patients remains challenging,” she said. “Recommendations for anticoagulation managements vary based on the presence of additional risk factors and which guidelines are followed.”

In the ENGAGE AF-TIMI 48 trial, 21,105 patients with documented AFib within the previous 12 months were randomized to standard-care warfarin or high-dose edoxaban (60 mg daily) or low-dose edoxaban (30 mg daily). The edoxaban dose was reduced by 50% if creatinine clearance reached 30-50 mL/min, patient weight reached 60 kg or less, or there was concomitant use of a P-glycoprotein inhibitor (N Engl J Med. 2013;369:2093-104). The median follow-up was 2.8 years, and the primary efficacy endpoint was stroke or systemic embolic events (SEEs). The primary safety endpoint was major bleeding, as defined by the International Society on Thrombosis and Haemostasis criteria.

The findings showed that edoxaban was noninferior to warfarin in preventing stroke/SEEs. It also significantly reduced major bleeding, cardiovascular death, and net outcomes. “Therefore, the higher dose of edoxaban was approved globally for treating patients with AFib,” Dr. Plitt said. “The lower-dose regimen was not approved because there was less protection from ischemic stroke, compared with warfarin.”

For the current subanalysis, Dr. Plitt and colleagues set out to further evaluate outcomes of patients enrolled in the ENGAGE AF-TIMI 48 trial, excluding those who were in the low-dose edoxaban group. The presence or absence of diabetes was determined by the local investigator at randomization. The investigators further stratified patients into insulin-treated and non–insulin treated groups and used multivariate Cox regression models to adjust for baseline characteristics across the groups stratified by diabetes status. Next, they analyzed edoxaban concentration, anti–factor Xa activity, and international normalized ratio data and compared outcomes of high-dose edoxaban with those of warfarin.

The primary endpoint and the primary safety endpoint of interest were the same as in the main ENGAGE AF-TIMI 48 trial. Key secondary endpoints included in the subanalysis were cardiovascular death, stroke/SEE, major adverse cardiovascular events (MACE, a composite of myocardial infarction, stroke, SEE, or death because of cardiovascular cause or bleeding), and all-cause death.

In all, 7,624 of the 21,105 patients in the ENGAGE AF-TIMI 48 trial had diabetes, for a rate of 36%. Most of the patients with diabetes did not require insulin (30%), while 6% did. There were fewer female patients with diabetes than without (37% vs. 39%, respectively). Of note was that history of prior stroke/transient ischemic attack was higher in the no-diabetes group than in the diabetes group (33% vs. 21%), as was congestive heart failure (63% vs. 48%).

The mean CHA2DS2-VASc score for predicting thromboembolic risk (0, low risk; greater than 1, high risk) was 4.6 in the diabetes group and 4.2 in the no-diabetes group. When diabetes was not included in the score, the mean CHA2DS2-VASc score was 3.6 in the diabetes group. “Because the trial entry criteria required a minimum CHADS2 score of 2, patients without diabetes were enriched with stroke risk factors other than diabetes,” Dr. Plitt said.

Adjusted outcomes from the subanalysis showed that the risk of stroke/SEE was similar between patients with and without diabetes (hazard ratio, 1.08). However, patients with diabetes were at higher adjusted risk for cardiovascular death than patients without diabetes (HR, 1.29), MACE (HR, 1.28), major bleed (HR, 1.28), and the net outcome of stroke, SEE, major bleed, or all-cause death (HR, 1.25).

The researchers also analyzed the pharmacodynamic and pharmacokinetic data of high-dose edoxaban, stratified by diabetes status. They found that the parameters were generally similar between patients with and without diabetes, including trough concentrations of edoxaban (34.3 and 37.2 ng/mL, respectively; P = .04), trough exogenous anti–factor Xa activity (0.59 and 0.68 IU/mL; P = .11), and the percentage change from baseline in the peak endogenous anti–factor Xa activity (P = .66). The percentage changes from baseline of the trough endogenous anti–factor Xa activity was slightly lower in patients with diabetes, compared with patients without diabetes (P less than .001). “However, these modest differences between the two groups are of unclear clinical significance,” Dr. Plitt said.

Results from the main ENGAGE AF-TIMI 48 showed that the rates of stroke/SEE were reduced by 13% on high-dose edoxaban. However, the subanalysis found no significant effect modification in the reduction in stroke/SEE with edoxaban, compared with warfarin, when stratified by diabetes status (reductions of 16% vs. 7% in the no-diabetes and diabetes groups, respectively; P for interaction = .54). The researchers also observed similar reductions with edoxaban in the risks of secondary outcomes when patients were stratified by diabetes status.

In another finding, patients with diabetes who were treated with insulin were at a higher adjusted risk for all outcomes, compared with those with diabetes who were not treated with insulin. This included stroke/SEE (HR, 1.44), cardiovascular-related death (HR, 1.83), MACE (HR, 1.78), major bleed (HR, 1.31), and net outcome (HR, 1.57).

Next, the researchers compared the study endpoints of high-dose edoxaban and warfarin, with and without insulin. “None of the efficacy, safety, or net outcomes demonstrated evidence of treatment effect modification related to the use of insulin among [patients with diabetes],” she said.

Dr. Plitt disclosed having received honoraria for educational activities from Bristol-Myers Squibb.

[email protected]

ORLANDO – It is good practice to consult with a pulmonary hypertension (PH) expert before referring a patient with sickle cell disease (SCD) for right-heart catheterization or PH evaluation, according to new American Society of Hematology guidelines for the screening and management of cardiopulmonary and kidney disease in patients with SCD.

Sharon Worcester/MDedge News

That “Good Practice” recommendation is one of several included in the evidence-based guidelines published Dec. 10 in Blood Advances and highlighted during a Special Education Session at the annual ASH meeting.

The guidelines provide 10 main recommendations intended to “support patients, clinicians, and other health care professionals in their decisions about screening, diagnosis, and management of cardiopulmonary and renal complications of SCD,” wrote Robert I. Liem, MD, of Ann & Robert H. Lurie Children’s Hospital of Chicago and colleagues.

The recommendations, agreed upon by a multidisciplinary guideline panel, relate to screening, diagnosis, and management of PH, pulmonary arterial hypertension (PAH), hypertension, proteinuria and chronic kidney disease, and venous thromboembolism (VTE). Most are “conditional,” as opposed to “strong,” because of a paucity of direct, high-quality outcomes data, and they are accompanied by the Good Practice Statements, descriptive remarks and caveats based on the available data, as well as suggestions for future research.

At the special ASH session, Ankit A. Desai, MD, highlighted some of the recommendations and discussed considerations for their practical application.

The Good Practice Statement on consulting a specialist before referring a patient for PH relates specifically to Recommendations 2a and 2b on the management of abnormal echocardiography, explained Dr. Desai of Indiana University, Indianapolis.

For asymptomatic children and adults with SCD and an isolated peak tricuspid regurgitant jet velocity (TRJV) of at least 2.5-2.9 m/s on echocardiography, the panel recommends against right-heart catheterization (Recommendation 2a, conditional), he said.

For children and adults with SCD and a peak TRJV of at least 2.5 m/s who also have a reduced 6-minute walk distance (6MWD) and/or elevated N-terminal proB-type natriuretic peptide (NT-proBNP), the panel supports right-heart catheterization (Recommendation 2b, conditional).

Sharon Worcester/MDedge News

Dr. Desai noted that the 2.5 m/s threshold was found to be suboptimal when used as the sole criteria for right-heart catheterization. Using that threshold alone is associated with “moderate to large” harms, such as starting inappropriate PH-specific therapies and/or performing unnecessary right-heart catheterization. However, when used in combination with 6MWD, the predictive capacity improved significantly, and the risk for potential harm was low, he explained.

Another Good Practice Statement included in the guidelines, and relevant to these recommendations on managing abnormal echocardiography, addresses the importance of basing decisions about the need for right-heart catheterization on echocardiograms obtained at steady state rather than during acute illness, such as during hospitalization for pain or acute chest syndrome.

This is in part because of technical factors, Dr. Desai said.

“We know that repeating [echocardiography] is something that should be considered in patients because ... results vary – sometimes quite a bit – from study to study,” he said.

As for the cutoff values for 6MWD and NT-proBNP, “a decent amount of literature” suggests that less than 333 m and less than 160 pg/ml, respectively, are good thresholds, he said.

“Importantly, this should all be taken in the context of good clinical judgment ... along with discussion with a PH expert,” he added.

The full guidelines are available, along with additional ASH guidelines on immune thrombocytopenia and prevention of venous thromboembolism in surgical hospitalized patients, at the ASH publications website.

Of note, the SCD guidelines on cardiopulmonary disease and kidney disease are one of five sets of SCD guidelines that have been in development; these are the first of those to be published. The remaining four sets of guidelines will address pain, cerebrovascular complications, transfusion, and hematopoietic stem cell transplant. All will be published in Blood Advances, and according to Dr. Liem, the transfusion medicine guidelines have been accepted and should be published in January 2020, followed by those for cerebrovascular complications. Publication of the pain and transplant guidelines are anticipated later in 2020.

Dr. Liem and Dr. Desai reported having no conflicts of interest.

[email protected]

ORLANDO – It is good practice to consult with a pulmonary hypertension (PH) expert before referring a patient with sickle cell disease (SCD) for right-heart catheterization or PH evaluation, according to new American Society of Hematology guidelines for the screening and management of cardiopulmonary and kidney disease in patients with SCD.

Sharon Worcester/MDedge News

That “Good Practice” recommendation is one of several included in the evidence-based guidelines published Dec. 10 in Blood Advances and highlighted during a Special Education Session at the annual ASH meeting.

The guidelines provide 10 main recommendations intended to “support patients, clinicians, and other health care professionals in their decisions about screening, diagnosis, and management of cardiopulmonary and renal complications of SCD,” wrote Robert I. Liem, MD, of Ann & Robert H. Lurie Children’s Hospital of Chicago and colleagues.

The recommendations, agreed upon by a multidisciplinary guideline panel, relate to screening, diagnosis, and management of PH, pulmonary arterial hypertension (PAH), hypertension, proteinuria and chronic kidney disease, and venous thromboembolism (VTE). Most are “conditional,” as opposed to “strong,” because of a paucity of direct, high-quality outcomes data, and they are accompanied by the Good Practice Statements, descriptive remarks and caveats based on the available data, as well as suggestions for future research.

At the special ASH session, Ankit A. Desai, MD, highlighted some of the recommendations and discussed considerations for their practical application.

The Good Practice Statement on consulting a specialist before referring a patient for PH relates specifically to Recommendations 2a and 2b on the management of abnormal echocardiography, explained Dr. Desai of Indiana University, Indianapolis.

For asymptomatic children and adults with SCD and an isolated peak tricuspid regurgitant jet velocity (TRJV) of at least 2.5-2.9 m/s on echocardiography, the panel recommends against right-heart catheterization (Recommendation 2a, conditional), he said.

For children and adults with SCD and a peak TRJV of at least 2.5 m/s who also have a reduced 6-minute walk distance (6MWD) and/or elevated N-terminal proB-type natriuretic peptide (NT-proBNP), the panel supports right-heart catheterization (Recommendation 2b, conditional).

Sharon Worcester/MDedge News

Dr. Desai noted that the 2.5 m/s threshold was found to be suboptimal when used as the sole criteria for right-heart catheterization. Using that threshold alone is associated with “moderate to large” harms, such as starting inappropriate PH-specific therapies and/or performing unnecessary right-heart catheterization. However, when used in combination with 6MWD, the predictive capacity improved significantly, and the risk for potential harm was low, he explained.

Another Good Practice Statement included in the guidelines, and relevant to these recommendations on managing abnormal echocardiography, addresses the importance of basing decisions about the need for right-heart catheterization on echocardiograms obtained at steady state rather than during acute illness, such as during hospitalization for pain or acute chest syndrome.

This is in part because of technical factors, Dr. Desai said.

“We know that repeating [echocardiography] is something that should be considered in patients because ... results vary – sometimes quite a bit – from study to study,” he said.

As for the cutoff values for 6MWD and NT-proBNP, “a decent amount of literature” suggests that less than 333 m and less than 160 pg/ml, respectively, are good thresholds, he said.

“Importantly, this should all be taken in the context of good clinical judgment ... along with discussion with a PH expert,” he added.

The full guidelines are available, along with additional ASH guidelines on immune thrombocytopenia and prevention of venous thromboembolism in surgical hospitalized patients, at the ASH publications website.

Of note, the SCD guidelines on cardiopulmonary disease and kidney disease are one of five sets of SCD guidelines that have been in development; these are the first of those to be published. The remaining four sets of guidelines will address pain, cerebrovascular complications, transfusion, and hematopoietic stem cell transplant. All will be published in Blood Advances, and according to Dr. Liem, the transfusion medicine guidelines have been accepted and should be published in January 2020, followed by those for cerebrovascular complications. Publication of the pain and transplant guidelines are anticipated later in 2020.

Dr. Liem and Dr. Desai reported having no conflicts of interest.

[email protected]

ORLANDO – It is good practice to consult with a pulmonary hypertension (PH) expert before referring a patient with sickle cell disease (SCD) for right-heart catheterization or PH evaluation, according to new American Society of Hematology guidelines for the screening and management of cardiopulmonary and kidney disease in patients with SCD.

Sharon Worcester/MDedge News

That “Good Practice” recommendation is one of several included in the evidence-based guidelines published Dec. 10 in Blood Advances and highlighted during a Special Education Session at the annual ASH meeting.

The guidelines provide 10 main recommendations intended to “support patients, clinicians, and other health care professionals in their decisions about screening, diagnosis, and management of cardiopulmonary and renal complications of SCD,” wrote Robert I. Liem, MD, of Ann & Robert H. Lurie Children’s Hospital of Chicago and colleagues.

The recommendations, agreed upon by a multidisciplinary guideline panel, relate to screening, diagnosis, and management of PH, pulmonary arterial hypertension (PAH), hypertension, proteinuria and chronic kidney disease, and venous thromboembolism (VTE). Most are “conditional,” as opposed to “strong,” because of a paucity of direct, high-quality outcomes data, and they are accompanied by the Good Practice Statements, descriptive remarks and caveats based on the available data, as well as suggestions for future research.

At the special ASH session, Ankit A. Desai, MD, highlighted some of the recommendations and discussed considerations for their practical application.

The Good Practice Statement on consulting a specialist before referring a patient for PH relates specifically to Recommendations 2a and 2b on the management of abnormal echocardiography, explained Dr. Desai of Indiana University, Indianapolis.

For asymptomatic children and adults with SCD and an isolated peak tricuspid regurgitant jet velocity (TRJV) of at least 2.5-2.9 m/s on echocardiography, the panel recommends against right-heart catheterization (Recommendation 2a, conditional), he said.

For children and adults with SCD and a peak TRJV of at least 2.5 m/s who also have a reduced 6-minute walk distance (6MWD) and/or elevated N-terminal proB-type natriuretic peptide (NT-proBNP), the panel supports right-heart catheterization (Recommendation 2b, conditional).

Sharon Worcester/MDedge News

Dr. Desai noted that the 2.5 m/s threshold was found to be suboptimal when used as the sole criteria for right-heart catheterization. Using that threshold alone is associated with “moderate to large” harms, such as starting inappropriate PH-specific therapies and/or performing unnecessary right-heart catheterization. However, when used in combination with 6MWD, the predictive capacity improved significantly, and the risk for potential harm was low, he explained.

Another Good Practice Statement included in the guidelines, and relevant to these recommendations on managing abnormal echocardiography, addresses the importance of basing decisions about the need for right-heart catheterization on echocardiograms obtained at steady state rather than during acute illness, such as during hospitalization for pain or acute chest syndrome.

This is in part because of technical factors, Dr. Desai said.

“We know that repeating [echocardiography] is something that should be considered in patients because ... results vary – sometimes quite a bit – from study to study,” he said.

As for the cutoff values for 6MWD and NT-proBNP, “a decent amount of literature” suggests that less than 333 m and less than 160 pg/ml, respectively, are good thresholds, he said.

“Importantly, this should all be taken in the context of good clinical judgment ... along with discussion with a PH expert,” he added.

The full guidelines are available, along with additional ASH guidelines on immune thrombocytopenia and prevention of venous thromboembolism in surgical hospitalized patients, at the ASH publications website.

Of note, the SCD guidelines on cardiopulmonary disease and kidney disease are one of five sets of SCD guidelines that have been in development; these are the first of those to be published. The remaining four sets of guidelines will address pain, cerebrovascular complications, transfusion, and hematopoietic stem cell transplant. All will be published in Blood Advances, and according to Dr. Liem, the transfusion medicine guidelines have been accepted and should be published in January 2020, followed by those for cerebrovascular complications. Publication of the pain and transplant guidelines are anticipated later in 2020.

Dr. Liem and Dr. Desai reported having no conflicts of interest.

[email protected]