The American Society of Echocardiography (ASE) has issued a statement on protecting patients and echocardiography service providers during the COVID-19 pandemic.

Given the risk for cardiovascular complications associated with COVID-19, echocardiographic services will likely be needed for patients with suspected or confirmed COVID-19, meaning echo providers will be exposed to SARS-CoV-2, write the statement authors, led by James N. Kirkpatrick, MD, director of the echocardiography laboratory at University of Washington Medical Center in Seattle.

The statement was published online April 6 in the Journal of the American College of Cardiology.

The authors say the statement is intended to help guide the practice of echocardiography in this “challenging time.” It was developed with input from a variety of echocardiography providers and institutions who have experience with the COVID-19, or have been “actively and thoughtfully preparing for it.”

Who, When, Where, and How

The statement covers triaging and decision pathways for handling requests for echocardiography, as well as indications and recommended procedures, in cases of suspected or confirmed COVID-19.

Among the recommendations:

• Only perform transthoracic echocardiograms (TTE), stress echocardiograms, and transesophageal echocardiograms (TEE) if they are expected to provide clinical benefit. Appropriate-use criteria represent the first decision point as to whether an echocardiographic test should be performed.
• Determine which studies are “elective” and reschedule them, performing all others. Identify “nonelective” (urgent/emergent) indications and defer all others.
• Determine the clinical benefit of echocardiography for symptomatic patients whose SARS-CoV-2 status is unknown.
• Cautiously consider the benefit of a TEE examination weighed against the risk for exposure of healthcare personnel to aerosolization in a patient with suspected or confirmed COVID-19.
• Postpone or cancel TEEs if an alternative imaging modality can provide the necessary information.
• Note that treadmill or bicycle stress echo tests in patients with COVID-19 may lead to exposure because of deep breathing and/or coughing during exercise. These tests should generally be deferred or converted to a pharmacologic stress echo.
   

   

The ASE statement also provides advice on safe imaging protocol and adequate personal protection measures.

“In addition to limiting the number of echocardiography practitioners involved in scanning, consideration should be given to limiting the exposure of staff who may be particularly susceptible to severe complications of COVID-19,” the ASE advises.

Staff who are older than 60 years, who have chronic conditions, are immunocompromised or are pregnant may wish to avoid contact with patients suspected or confirmed to have COVID-19.

It’s also important to realize the risk for transmission in reading rooms. “Keyboards, monitors, mice, chairs, phones, desktops, and door knobs should be frequently cleaned, and ventilation provided wherever possible,” the ASE advises. When the echo lab reading room is located in a high-traffic area, remote review of images or via webinar might be advisable, they suggest.

Summing up, Kirkland and colleagues say providing echocardiographic service “remains crucial in this difficult time of the SARS-CoV-2 outbreak. Working together, we can continue to provide high-quality care while minimizing risk to ourselves, our patients, and the public at large. Carefully considering ‘Whom to Image’, ‘Where to Image’ and ‘How to Image’ has the potential to reduce the risks of transmission.”

The authors note that the statements and recommendations are primarily based on expert opinion rather than on scientifically verified data and are subject to change as the COVID-19 outbreak continues to evolve and new data emerges.
 

This article first appeared on Medscape.com.

The American Society of Echocardiography (ASE) has issued a statement on protecting patients and echocardiography service providers during the COVID-19 pandemic.

Given the risk for cardiovascular complications associated with COVID-19, echocardiographic services will likely be needed for patients with suspected or confirmed COVID-19, meaning echo providers will be exposed to SARS-CoV-2, write the statement authors, led by James N. Kirkpatrick, MD, director of the echocardiography laboratory at University of Washington Medical Center in Seattle.

The statement was published online April 6 in the Journal of the American College of Cardiology.

The authors say the statement is intended to help guide the practice of echocardiography in this “challenging time.” It was developed with input from a variety of echocardiography providers and institutions who have experience with the COVID-19, or have been “actively and thoughtfully preparing for it.”

Who, When, Where, and How

The statement covers triaging and decision pathways for handling requests for echocardiography, as well as indications and recommended procedures, in cases of suspected or confirmed COVID-19.

Among the recommendations:

• Only perform transthoracic echocardiograms (TTE), stress echocardiograms, and transesophageal echocardiograms (TEE) if they are expected to provide clinical benefit. Appropriate-use criteria represent the first decision point as to whether an echocardiographic test should be performed.
• Determine which studies are “elective” and reschedule them, performing all others. Identify “nonelective” (urgent/emergent) indications and defer all others.
• Determine the clinical benefit of echocardiography for symptomatic patients whose SARS-CoV-2 status is unknown.
• Cautiously consider the benefit of a TEE examination weighed against the risk for exposure of healthcare personnel to aerosolization in a patient with suspected or confirmed COVID-19.
• Postpone or cancel TEEs if an alternative imaging modality can provide the necessary information.
• Note that treadmill or bicycle stress echo tests in patients with COVID-19 may lead to exposure because of deep breathing and/or coughing during exercise. These tests should generally be deferred or converted to a pharmacologic stress echo.
   

   

The ASE statement also provides advice on safe imaging protocol and adequate personal protection measures.

“In addition to limiting the number of echocardiography practitioners involved in scanning, consideration should be given to limiting the exposure of staff who may be particularly susceptible to severe complications of COVID-19,” the ASE advises.

Staff who are older than 60 years, who have chronic conditions, are immunocompromised or are pregnant may wish to avoid contact with patients suspected or confirmed to have COVID-19.

It’s also important to realize the risk for transmission in reading rooms. “Keyboards, monitors, mice, chairs, phones, desktops, and door knobs should be frequently cleaned, and ventilation provided wherever possible,” the ASE advises. When the echo lab reading room is located in a high-traffic area, remote review of images or via webinar might be advisable, they suggest.

Summing up, Kirkland and colleagues say providing echocardiographic service “remains crucial in this difficult time of the SARS-CoV-2 outbreak. Working together, we can continue to provide high-quality care while minimizing risk to ourselves, our patients, and the public at large. Carefully considering ‘Whom to Image’, ‘Where to Image’ and ‘How to Image’ has the potential to reduce the risks of transmission.”

The authors note that the statements and recommendations are primarily based on expert opinion rather than on scientifically verified data and are subject to change as the COVID-19 outbreak continues to evolve and new data emerges.
 

This article first appeared on Medscape.com.

The American Society of Echocardiography (ASE) has issued a statement on protecting patients and echocardiography service providers during the COVID-19 pandemic.

Given the risk for cardiovascular complications associated with COVID-19, echocardiographic services will likely be needed for patients with suspected or confirmed COVID-19, meaning echo providers will be exposed to SARS-CoV-2, write the statement authors, led by James N. Kirkpatrick, MD, director of the echocardiography laboratory at University of Washington Medical Center in Seattle.

The statement was published online April 6 in the Journal of the American College of Cardiology.

The authors say the statement is intended to help guide the practice of echocardiography in this “challenging time.” It was developed with input from a variety of echocardiography providers and institutions who have experience with the COVID-19, or have been “actively and thoughtfully preparing for it.”

Who, When, Where, and How

The statement covers triaging and decision pathways for handling requests for echocardiography, as well as indications and recommended procedures, in cases of suspected or confirmed COVID-19.

Among the recommendations:

• Only perform transthoracic echocardiograms (TTE), stress echocardiograms, and transesophageal echocardiograms (TEE) if they are expected to provide clinical benefit. Appropriate-use criteria represent the first decision point as to whether an echocardiographic test should be performed.
• Determine which studies are “elective” and reschedule them, performing all others. Identify “nonelective” (urgent/emergent) indications and defer all others.
• Determine the clinical benefit of echocardiography for symptomatic patients whose SARS-CoV-2 status is unknown.
• Cautiously consider the benefit of a TEE examination weighed against the risk for exposure of healthcare personnel to aerosolization in a patient with suspected or confirmed COVID-19.
• Postpone or cancel TEEs if an alternative imaging modality can provide the necessary information.
• Note that treadmill or bicycle stress echo tests in patients with COVID-19 may lead to exposure because of deep breathing and/or coughing during exercise. These tests should generally be deferred or converted to a pharmacologic stress echo.
   

   

The ASE statement also provides advice on safe imaging protocol and adequate personal protection measures.

“In addition to limiting the number of echocardiography practitioners involved in scanning, consideration should be given to limiting the exposure of staff who may be particularly susceptible to severe complications of COVID-19,” the ASE advises.

Staff who are older than 60 years, who have chronic conditions, are immunocompromised or are pregnant may wish to avoid contact with patients suspected or confirmed to have COVID-19.

It’s also important to realize the risk for transmission in reading rooms. “Keyboards, monitors, mice, chairs, phones, desktops, and door knobs should be frequently cleaned, and ventilation provided wherever possible,” the ASE advises. When the echo lab reading room is located in a high-traffic area, remote review of images or via webinar might be advisable, they suggest.

Summing up, Kirkland and colleagues say providing echocardiographic service “remains crucial in this difficult time of the SARS-CoV-2 outbreak. Working together, we can continue to provide high-quality care while minimizing risk to ourselves, our patients, and the public at large. Carefully considering ‘Whom to Image’, ‘Where to Image’ and ‘How to Image’ has the potential to reduce the risks of transmission.”

The authors note that the statements and recommendations are primarily based on expert opinion rather than on scientifically verified data and are subject to change as the COVID-19 outbreak continues to evolve and new data emerges.
 

This article first appeared on Medscape.com.

Family physician Frank Maselli, MD, saw approximately 30 patients a day in his office in the Bronx before COVID-19. But New York City has become a hot spot for the virus that has claimed the lives of the lives of more than 40,000 people nationwide.

Now Maselli and the other 10 physicians in the practice each treat only eight or nine patients a day via telemedicine. He spends most of his time on the phone answering patients’ questions about COVID-19 symptoms and potential exposure. Although he tries to bill for telemedicine and phone calls, he says many commercial payers reject the claims because their processing systems aren’t updated to reflect new coverage policies. He has enough cash in reserve to cover two payrolls, but he knows he needs a backup plan if patient volumes continue to decrease indefinitely.

“Our doctors will take a pay cut before we let people go,” says Maselli. “So far we’re OK because we’re getting paid for things we did two months ago before all of this happened.”

Ninety-seven percent of medical practices have experienced a negative financial impact directly or indirectly related to the COVID-19 pandemic, according to new data from the Medical Group Management Association (MGMA). On average, practices report a 60% decrease in patient volume and a 55% decrease in revenue since the beginning of the public health emergency.
 

Four options for financial assistance

However, there are ways to offset revenue loss and remain financially viable during the economic uncertainty of the COVID-19 pandemic. Options include the US Small Business Administration’s (SBA) Paycheck Protection Program; the SBA’s Emergency Economic Injury Disaster Loan (EIDL); Medicare’s advanced payment program; and an SBA Coronavirus Economic Stabilization Act (CESA) loan. These are in addition to several other strategies aimed at reducing costs and improving revenue.

1. Maselli, for example, applied for the Paycheck Protection Program, a short-term loan that helps small businesses (i.e., for physician offices, those with an annual revenue of under $12 million) keep staff employed during the COVID-19 crisis. The loan covers a variety of costs, including payroll, rent, utilities, mortgage interest, and interest on any other debt obligations incurred before February 15 of this year.

“We have no idea if this is coming and when, but it would be a big help,” he adds.

(As of press time, the Paycheck Protection Program had stopped accepting applications, having reached the limit of its $349 billion budget. Congress must now agree on legislation to add additional funding to assist small businesses.)

Practices can take out a loan of up to 2.5 times the average monthly payroll (excluding payroll for those making more than $100,000 annually) with a cap of $10 million. For example, if the average monthly payroll is $10,000 – and no employees earn more than $100,000 annually – the maximum loan amount is $25,000.

Practices approved for this loan can expect to receive the funds from their SBA-approved lender within 10 calendar days of the date of loan approval. Although it’s technically a loan, the good news is that it doesn’t need to be repaid if the practice complies with all of the loan requirements – particularly these two: The practice uses at least 75% of the loan specifically for payroll, and the practice keeps employees on the payroll (or rehire, when necessary) for 8 weeks after the loan origination date.

Forgiveness is reduced if full-time headcount declines, or if salaries and wages decrease. If a practice does need to repay all or a portion of the loan, it must do so within 2 years at an interest rate of 1%, and payments are deferred for 6 months.

Andrew D. McDonald, FACHE, practice leader of health care consulting at LBMC Healthcare, says it behooves practices to apply for this loan because it’s essentially free money during a time when revenue may be at an all-time low. “While the devil is in the details, on the surface, the paycheck protection funds appear to be a no-brainer. However, each practice will need to confirm with their lender that it’s a solid decision.”

One challenge with this loan is that some banks weren’t necessarily ready to accept applications on April 3, and many continue to lag behind in processing these applications.

2. A second option is the SBA’s EIDL, a low-interest, long-term loan (capped at 3.75% for small businesses) that practices with 500 or fewer employees can use to pay fixed debts, payrolls, accounts payable, and other bills that could have been paid had the disaster not occurred. Borrowers can ask for up to $2 million, and the maximum term of this loan is 30 years, though the overall process for obtaining these loans will depend on the lender.

Practices have until December 16 to apply for this loan. They can also apply for an expedited disbursement (i.e., an Economic Injury Disaster Advance) of up to $10,000 that’s paid within 3 days of the request.

3. A third option is Medicare’s COVID-19 advanced payment program. Under this program, eligible physicians are those who:

• Billed Medicare for claims within 180 days prior to the date of the request
• Are financially solvent (i.e., aren’t in bankruptcy)
• Are free from any active medical review or program integrity investigations
• Are in good standing with Medicare (i.e., don’t have an outstanding delinquent Medicare overpayment)

If physicians meet this criteria, they can ask their Medicare Administrative Contractor (MAC) to provide an advanced payment of up to 100% of the Medicare payment amount based on a 3-month lookback period.

Once requested, MACs will issue payment within 7 calendar days from the date of the request. Repayment will occur in the form of automatic recoupments beginning 120 days after the advanced payment is received. Medicare has already approved more than 21,000 requests totaling more than $51 billion. CMS has provided a fact sheet to learn more about how to request an accelerated payment.

“The key is that you need to repay this, so you want to set a reasonable goal,” says Sarah Hostetter, senior consultant at Advisory Board, a health care research & data consulting firm. She says practices should consider what they’ll realistically be able to repay within 120 days.

4. A fourth option – specifically for mid-size practices – is a CESA loan, the details of which have yet to be announced, that will enable practices to access funds with an annualized rate no greater than 2% and with no principal or interest due for at least 6 months. The CARES Act, signed into law 3 weeks ago, provides $454 billion for this program.
 

Selecting the right option for your practice

Which singular option – or combination of options – is best for your practice? McDonald says to ask these questions:

• How well are patient volumes holding up?
• How well are physicians pivoting to telehealth?
• What is the overall economic loss?
• What are the available liquid assets, and how long can the practice maintain its financial viability over the next couple of months and beyond?

Cheryl Mongillo, MBA, administrative director of two independent family practices in Delaware, applied for both the Paycheck Protection Program and Medicare advanced payments because she’s worried about being able to pay staff while also covering costs related to personal protective equipment, medical waste, and cleaning, all of which have tripled since the pandemic began. One of the practices includes one physician and four nurse practitioners. The other includes five physicians and three nurse practitioners. In total, both practices employ 35 additional staff.

“I want our staff to know how much we care about them. My hope is that after this is over, our business will pick back up pretty quickly,” she adds. “However, until I can get the business back, I needed something to keep us afloat.”

Others are being more cautious. Crystal Bruning, practice manager at an Ob/Gyn clinic in Orlando, Florida, says her practice applied for the Paycheck Protection Program but is waiting another month or so before deciding whether it will also take advantage of Medicare advanced payments.

The practice is still trying to assess the true financial impact of its 30% reduction in patient volume. Bruning says the advanced payments wouldn’t amount to much anyway because only 10% of the practice’s patients have Medicare.
 

Making tough financial decisions while awaiting assistance

Kansas-based family physician Jennifer Bacani McKenney, MD, says she hasn’t paid herself a salary in weeks because of the revenue loss her practice has incurred.

“I want to make sure we can pay [all 12] employees,” she says. “In my family, we have two incomes, and we’re pretty good at saving money. However, I know not every physician can afford to do this.”

Although McKenney’s practice has seen a 75% reduction in patient volume, staff continue to provide virtual visits – including Zoom-based nursing home visits – phone visits, and in-person visits for acute illnesses. They also provide curbside immunizations. Still, long-term revenue loss is a concern. “I have a threshold in mind based on what we have in reserves,” she says. “If we hit that point, we would need to talk about a loan or Medicare advanced payments.”

Arkansas-based family physician Lonnie S. Robinson, MD, says he immediately applied for the Paycheck Protection Program after it was announced. “We also made sure we had a line of credit with our local bank during the very first discussions about what the pandemic would mean for our revenue streams,” he says.

However, because he’s in a rural area of the state, he continues to struggle with telemedicine due to broadband and connectivity challenges. Cash flow is another challenge because a lot of insurance companies are waiving copayments.

“I didn’t realize the amount of money we collect immediately from the patient,” he says. “This was a substantial revenue stream, and it was immediate revenue – not revenue waiting on a claim to be paid.”

Illinois-based family physician Deborah L. Winiger, MD, says she also applied for the Paycheck Protection Program but in the meantime had to reduce staff hours by a third because her patient volume dropped by more than half. She will also encourage staff to pursue temporary positions at a local hospital if the federal funds don’t materialize.

Kelly Shackleton, practice manager at a New York-based internal medicine practice, says she laid off 7 of her 16 staff members (including lab technicians, licensed practical nurses, billers, a referral specialist, and a file clerk) due to a 70% decrease in patient volume.

“I didn’t lay them all off at once,” she says. “I kept them until things were all caught up in each department. I plan to get them all back when the time is right, but I want to be sure to keep the practice afloat so they have a place to return to.” If the Paycheck Protection Program for which she applied comes through, then she will rehire them. She also applied for Medicare advanced payments and increased the practice’s line of credit.
 

Bill properly – and for everything you are still doing

Accurate and complete coding is critical during this time of financial instability, says Maselli. “I keep telling doctors to bill for everything they do,” he says. This includes phone calls between patients and physicians or other qualified healthcare providers (CPT codes 99441-99443). Note that these are time-based codes, requiring a minimum of five minutes of medical discussion.

Remote physiologic monitoring (including monitoring a patient’s oxygen saturation levels using pulse oximetry), virtual check-ins, and online digital evaluation and management services are also covered by Medicare and some commercial payers.

Other good news is that the Centers for Medicare & Medicaid Services added more than 80 additional services that providers can furnish using telehealth, including new patient office visits, home visits, prolonged office visits, smoking and tobacco cessation counseling, annual depression and alcohol screenings, advanced care planning, and much more.

Mongillo, the family practice administrator in Delaware, agrees that physicians need to bill for as many services as possible. At one of the family medicine practices she manages, physicians perform wellness visits, when appropriate, if patients are already coming into the office for another ailment.

Also look for ways to cut costs. For example, Mongillo was able to renegotiate the practice’s telemedicine contract after she received several proposals from other vendors offering three months of complimentary service. Shackleton discontinued provider dictation services to save money.

Physicians need to take a hard look at what’s going on to help them sustain their business through times of uncertainty, says Advisory Board’s Hostetter. “Now is the time to evaluate options and figure out what’s right for your practice,” she adds.

This article first appeared on Medscape.com.

Family physician Frank Maselli, MD, saw approximately 30 patients a day in his office in the Bronx before COVID-19. But New York City has become a hot spot for the virus that has claimed the lives of the lives of more than 40,000 people nationwide.

Now Maselli and the other 10 physicians in the practice each treat only eight or nine patients a day via telemedicine. He spends most of his time on the phone answering patients’ questions about COVID-19 symptoms and potential exposure. Although he tries to bill for telemedicine and phone calls, he says many commercial payers reject the claims because their processing systems aren’t updated to reflect new coverage policies. He has enough cash in reserve to cover two payrolls, but he knows he needs a backup plan if patient volumes continue to decrease indefinitely.

“Our doctors will take a pay cut before we let people go,” says Maselli. “So far we’re OK because we’re getting paid for things we did two months ago before all of this happened.”

Ninety-seven percent of medical practices have experienced a negative financial impact directly or indirectly related to the COVID-19 pandemic, according to new data from the Medical Group Management Association (MGMA). On average, practices report a 60% decrease in patient volume and a 55% decrease in revenue since the beginning of the public health emergency.
 

Four options for financial assistance

However, there are ways to offset revenue loss and remain financially viable during the economic uncertainty of the COVID-19 pandemic. Options include the US Small Business Administration’s (SBA) Paycheck Protection Program; the SBA’s Emergency Economic Injury Disaster Loan (EIDL); Medicare’s advanced payment program; and an SBA Coronavirus Economic Stabilization Act (CESA) loan. These are in addition to several other strategies aimed at reducing costs and improving revenue.

1. Maselli, for example, applied for the Paycheck Protection Program, a short-term loan that helps small businesses (i.e., for physician offices, those with an annual revenue of under $12 million) keep staff employed during the COVID-19 crisis. The loan covers a variety of costs, including payroll, rent, utilities, mortgage interest, and interest on any other debt obligations incurred before February 15 of this year.

“We have no idea if this is coming and when, but it would be a big help,” he adds.

(As of press time, the Paycheck Protection Program had stopped accepting applications, having reached the limit of its $349 billion budget. Congress must now agree on legislation to add additional funding to assist small businesses.)

Practices can take out a loan of up to 2.5 times the average monthly payroll (excluding payroll for those making more than $100,000 annually) with a cap of $10 million. For example, if the average monthly payroll is $10,000 – and no employees earn more than $100,000 annually – the maximum loan amount is $25,000.

Practices approved for this loan can expect to receive the funds from their SBA-approved lender within 10 calendar days of the date of loan approval. Although it’s technically a loan, the good news is that it doesn’t need to be repaid if the practice complies with all of the loan requirements – particularly these two: The practice uses at least 75% of the loan specifically for payroll, and the practice keeps employees on the payroll (or rehire, when necessary) for 8 weeks after the loan origination date.

Forgiveness is reduced if full-time headcount declines, or if salaries and wages decrease. If a practice does need to repay all or a portion of the loan, it must do so within 2 years at an interest rate of 1%, and payments are deferred for 6 months.

Andrew D. McDonald, FACHE, practice leader of health care consulting at LBMC Healthcare, says it behooves practices to apply for this loan because it’s essentially free money during a time when revenue may be at an all-time low. “While the devil is in the details, on the surface, the paycheck protection funds appear to be a no-brainer. However, each practice will need to confirm with their lender that it’s a solid decision.”

One challenge with this loan is that some banks weren’t necessarily ready to accept applications on April 3, and many continue to lag behind in processing these applications.

2. A second option is the SBA’s EIDL, a low-interest, long-term loan (capped at 3.75% for small businesses) that practices with 500 or fewer employees can use to pay fixed debts, payrolls, accounts payable, and other bills that could have been paid had the disaster not occurred. Borrowers can ask for up to $2 million, and the maximum term of this loan is 30 years, though the overall process for obtaining these loans will depend on the lender.

Practices have until December 16 to apply for this loan. They can also apply for an expedited disbursement (i.e., an Economic Injury Disaster Advance) of up to $10,000 that’s paid within 3 days of the request.

3. A third option is Medicare’s COVID-19 advanced payment program. Under this program, eligible physicians are those who:

• Billed Medicare for claims within 180 days prior to the date of the request
• Are financially solvent (i.e., aren’t in bankruptcy)
• Are free from any active medical review or program integrity investigations
• Are in good standing with Medicare (i.e., don’t have an outstanding delinquent Medicare overpayment)

If physicians meet this criteria, they can ask their Medicare Administrative Contractor (MAC) to provide an advanced payment of up to 100% of the Medicare payment amount based on a 3-month lookback period.

Once requested, MACs will issue payment within 7 calendar days from the date of the request. Repayment will occur in the form of automatic recoupments beginning 120 days after the advanced payment is received. Medicare has already approved more than 21,000 requests totaling more than $51 billion. CMS has provided a fact sheet to learn more about how to request an accelerated payment.

“The key is that you need to repay this, so you want to set a reasonable goal,” says Sarah Hostetter, senior consultant at Advisory Board, a health care research & data consulting firm. She says practices should consider what they’ll realistically be able to repay within 120 days.

4. A fourth option – specifically for mid-size practices – is a CESA loan, the details of which have yet to be announced, that will enable practices to access funds with an annualized rate no greater than 2% and with no principal or interest due for at least 6 months. The CARES Act, signed into law 3 weeks ago, provides $454 billion for this program.
 

Selecting the right option for your practice

Which singular option – or combination of options – is best for your practice? McDonald says to ask these questions:

• How well are patient volumes holding up?
• How well are physicians pivoting to telehealth?
• What is the overall economic loss?
• What are the available liquid assets, and how long can the practice maintain its financial viability over the next couple of months and beyond?

Cheryl Mongillo, MBA, administrative director of two independent family practices in Delaware, applied for both the Paycheck Protection Program and Medicare advanced payments because she’s worried about being able to pay staff while also covering costs related to personal protective equipment, medical waste, and cleaning, all of which have tripled since the pandemic began. One of the practices includes one physician and four nurse practitioners. The other includes five physicians and three nurse practitioners. In total, both practices employ 35 additional staff.

“I want our staff to know how much we care about them. My hope is that after this is over, our business will pick back up pretty quickly,” she adds. “However, until I can get the business back, I needed something to keep us afloat.”

Others are being more cautious. Crystal Bruning, practice manager at an Ob/Gyn clinic in Orlando, Florida, says her practice applied for the Paycheck Protection Program but is waiting another month or so before deciding whether it will also take advantage of Medicare advanced payments.

The practice is still trying to assess the true financial impact of its 30% reduction in patient volume. Bruning says the advanced payments wouldn’t amount to much anyway because only 10% of the practice’s patients have Medicare.
 

Making tough financial decisions while awaiting assistance

Kansas-based family physician Jennifer Bacani McKenney, MD, says she hasn’t paid herself a salary in weeks because of the revenue loss her practice has incurred.

“I want to make sure we can pay [all 12] employees,” she says. “In my family, we have two incomes, and we’re pretty good at saving money. However, I know not every physician can afford to do this.”

Although McKenney’s practice has seen a 75% reduction in patient volume, staff continue to provide virtual visits – including Zoom-based nursing home visits – phone visits, and in-person visits for acute illnesses. They also provide curbside immunizations. Still, long-term revenue loss is a concern. “I have a threshold in mind based on what we have in reserves,” she says. “If we hit that point, we would need to talk about a loan or Medicare advanced payments.”

Arkansas-based family physician Lonnie S. Robinson, MD, says he immediately applied for the Paycheck Protection Program after it was announced. “We also made sure we had a line of credit with our local bank during the very first discussions about what the pandemic would mean for our revenue streams,” he says.

However, because he’s in a rural area of the state, he continues to struggle with telemedicine due to broadband and connectivity challenges. Cash flow is another challenge because a lot of insurance companies are waiving copayments.

“I didn’t realize the amount of money we collect immediately from the patient,” he says. “This was a substantial revenue stream, and it was immediate revenue – not revenue waiting on a claim to be paid.”

Illinois-based family physician Deborah L. Winiger, MD, says she also applied for the Paycheck Protection Program but in the meantime had to reduce staff hours by a third because her patient volume dropped by more than half. She will also encourage staff to pursue temporary positions at a local hospital if the federal funds don’t materialize.

Kelly Shackleton, practice manager at a New York-based internal medicine practice, says she laid off 7 of her 16 staff members (including lab technicians, licensed practical nurses, billers, a referral specialist, and a file clerk) due to a 70% decrease in patient volume.

“I didn’t lay them all off at once,” she says. “I kept them until things were all caught up in each department. I plan to get them all back when the time is right, but I want to be sure to keep the practice afloat so they have a place to return to.” If the Paycheck Protection Program for which she applied comes through, then she will rehire them. She also applied for Medicare advanced payments and increased the practice’s line of credit.
 

Bill properly – and for everything you are still doing

Accurate and complete coding is critical during this time of financial instability, says Maselli. “I keep telling doctors to bill for everything they do,” he says. This includes phone calls between patients and physicians or other qualified healthcare providers (CPT codes 99441-99443). Note that these are time-based codes, requiring a minimum of five minutes of medical discussion.

Remote physiologic monitoring (including monitoring a patient’s oxygen saturation levels using pulse oximetry), virtual check-ins, and online digital evaluation and management services are also covered by Medicare and some commercial payers.

Other good news is that the Centers for Medicare & Medicaid Services added more than 80 additional services that providers can furnish using telehealth, including new patient office visits, home visits, prolonged office visits, smoking and tobacco cessation counseling, annual depression and alcohol screenings, advanced care planning, and much more.

Mongillo, the family practice administrator in Delaware, agrees that physicians need to bill for as many services as possible. At one of the family medicine practices she manages, physicians perform wellness visits, when appropriate, if patients are already coming into the office for another ailment.

Also look for ways to cut costs. For example, Mongillo was able to renegotiate the practice’s telemedicine contract after she received several proposals from other vendors offering three months of complimentary service. Shackleton discontinued provider dictation services to save money.

Physicians need to take a hard look at what’s going on to help them sustain their business through times of uncertainty, says Advisory Board’s Hostetter. “Now is the time to evaluate options and figure out what’s right for your practice,” she adds.

This article first appeared on Medscape.com.

Family physician Frank Maselli, MD, saw approximately 30 patients a day in his office in the Bronx before COVID-19. But New York City has become a hot spot for the virus that has claimed the lives of the lives of more than 40,000 people nationwide.

Now Maselli and the other 10 physicians in the practice each treat only eight or nine patients a day via telemedicine. He spends most of his time on the phone answering patients’ questions about COVID-19 symptoms and potential exposure. Although he tries to bill for telemedicine and phone calls, he says many commercial payers reject the claims because their processing systems aren’t updated to reflect new coverage policies. He has enough cash in reserve to cover two payrolls, but he knows he needs a backup plan if patient volumes continue to decrease indefinitely.

“Our doctors will take a pay cut before we let people go,” says Maselli. “So far we’re OK because we’re getting paid for things we did two months ago before all of this happened.”

Ninety-seven percent of medical practices have experienced a negative financial impact directly or indirectly related to the COVID-19 pandemic, according to new data from the Medical Group Management Association (MGMA). On average, practices report a 60% decrease in patient volume and a 55% decrease in revenue since the beginning of the public health emergency.
 

Four options for financial assistance

However, there are ways to offset revenue loss and remain financially viable during the economic uncertainty of the COVID-19 pandemic. Options include the US Small Business Administration’s (SBA) Paycheck Protection Program; the SBA’s Emergency Economic Injury Disaster Loan (EIDL); Medicare’s advanced payment program; and an SBA Coronavirus Economic Stabilization Act (CESA) loan. These are in addition to several other strategies aimed at reducing costs and improving revenue.

1. Maselli, for example, applied for the Paycheck Protection Program, a short-term loan that helps small businesses (i.e., for physician offices, those with an annual revenue of under $12 million) keep staff employed during the COVID-19 crisis. The loan covers a variety of costs, including payroll, rent, utilities, mortgage interest, and interest on any other debt obligations incurred before February 15 of this year.

“We have no idea if this is coming and when, but it would be a big help,” he adds.

(As of press time, the Paycheck Protection Program had stopped accepting applications, having reached the limit of its $349 billion budget. Congress must now agree on legislation to add additional funding to assist small businesses.)

Practices can take out a loan of up to 2.5 times the average monthly payroll (excluding payroll for those making more than $100,000 annually) with a cap of $10 million. For example, if the average monthly payroll is $10,000 – and no employees earn more than $100,000 annually – the maximum loan amount is $25,000.

Practices approved for this loan can expect to receive the funds from their SBA-approved lender within 10 calendar days of the date of loan approval. Although it’s technically a loan, the good news is that it doesn’t need to be repaid if the practice complies with all of the loan requirements – particularly these two: The practice uses at least 75% of the loan specifically for payroll, and the practice keeps employees on the payroll (or rehire, when necessary) for 8 weeks after the loan origination date.

Forgiveness is reduced if full-time headcount declines, or if salaries and wages decrease. If a practice does need to repay all or a portion of the loan, it must do so within 2 years at an interest rate of 1%, and payments are deferred for 6 months.

Andrew D. McDonald, FACHE, practice leader of health care consulting at LBMC Healthcare, says it behooves practices to apply for this loan because it’s essentially free money during a time when revenue may be at an all-time low. “While the devil is in the details, on the surface, the paycheck protection funds appear to be a no-brainer. However, each practice will need to confirm with their lender that it’s a solid decision.”

One challenge with this loan is that some banks weren’t necessarily ready to accept applications on April 3, and many continue to lag behind in processing these applications.

2. A second option is the SBA’s EIDL, a low-interest, long-term loan (capped at 3.75% for small businesses) that practices with 500 or fewer employees can use to pay fixed debts, payrolls, accounts payable, and other bills that could have been paid had the disaster not occurred. Borrowers can ask for up to $2 million, and the maximum term of this loan is 30 years, though the overall process for obtaining these loans will depend on the lender.

Practices have until December 16 to apply for this loan. They can also apply for an expedited disbursement (i.e., an Economic Injury Disaster Advance) of up to $10,000 that’s paid within 3 days of the request.

3. A third option is Medicare’s COVID-19 advanced payment program. Under this program, eligible physicians are those who:

• Billed Medicare for claims within 180 days prior to the date of the request
• Are financially solvent (i.e., aren’t in bankruptcy)
• Are free from any active medical review or program integrity investigations
• Are in good standing with Medicare (i.e., don’t have an outstanding delinquent Medicare overpayment)

If physicians meet this criteria, they can ask their Medicare Administrative Contractor (MAC) to provide an advanced payment of up to 100% of the Medicare payment amount based on a 3-month lookback period.

Once requested, MACs will issue payment within 7 calendar days from the date of the request. Repayment will occur in the form of automatic recoupments beginning 120 days after the advanced payment is received. Medicare has already approved more than 21,000 requests totaling more than $51 billion. CMS has provided a fact sheet to learn more about how to request an accelerated payment.

“The key is that you need to repay this, so you want to set a reasonable goal,” says Sarah Hostetter, senior consultant at Advisory Board, a health care research & data consulting firm. She says practices should consider what they’ll realistically be able to repay within 120 days.

4. A fourth option – specifically for mid-size practices – is a CESA loan, the details of which have yet to be announced, that will enable practices to access funds with an annualized rate no greater than 2% and with no principal or interest due for at least 6 months. The CARES Act, signed into law 3 weeks ago, provides $454 billion for this program.
 

Selecting the right option for your practice

Which singular option – or combination of options – is best for your practice? McDonald says to ask these questions:

• How well are patient volumes holding up?
• How well are physicians pivoting to telehealth?
• What is the overall economic loss?
• What are the available liquid assets, and how long can the practice maintain its financial viability over the next couple of months and beyond?

Cheryl Mongillo, MBA, administrative director of two independent family practices in Delaware, applied for both the Paycheck Protection Program and Medicare advanced payments because she’s worried about being able to pay staff while also covering costs related to personal protective equipment, medical waste, and cleaning, all of which have tripled since the pandemic began. One of the practices includes one physician and four nurse practitioners. The other includes five physicians and three nurse practitioners. In total, both practices employ 35 additional staff.

“I want our staff to know how much we care about them. My hope is that after this is over, our business will pick back up pretty quickly,” she adds. “However, until I can get the business back, I needed something to keep us afloat.”

Others are being more cautious. Crystal Bruning, practice manager at an Ob/Gyn clinic in Orlando, Florida, says her practice applied for the Paycheck Protection Program but is waiting another month or so before deciding whether it will also take advantage of Medicare advanced payments.

The practice is still trying to assess the true financial impact of its 30% reduction in patient volume. Bruning says the advanced payments wouldn’t amount to much anyway because only 10% of the practice’s patients have Medicare.
 

Making tough financial decisions while awaiting assistance

Kansas-based family physician Jennifer Bacani McKenney, MD, says she hasn’t paid herself a salary in weeks because of the revenue loss her practice has incurred.

“I want to make sure we can pay [all 12] employees,” she says. “In my family, we have two incomes, and we’re pretty good at saving money. However, I know not every physician can afford to do this.”

Although McKenney’s practice has seen a 75% reduction in patient volume, staff continue to provide virtual visits – including Zoom-based nursing home visits – phone visits, and in-person visits for acute illnesses. They also provide curbside immunizations. Still, long-term revenue loss is a concern. “I have a threshold in mind based on what we have in reserves,” she says. “If we hit that point, we would need to talk about a loan or Medicare advanced payments.”

Arkansas-based family physician Lonnie S. Robinson, MD, says he immediately applied for the Paycheck Protection Program after it was announced. “We also made sure we had a line of credit with our local bank during the very first discussions about what the pandemic would mean for our revenue streams,” he says.

However, because he’s in a rural area of the state, he continues to struggle with telemedicine due to broadband and connectivity challenges. Cash flow is another challenge because a lot of insurance companies are waiving copayments.

“I didn’t realize the amount of money we collect immediately from the patient,” he says. “This was a substantial revenue stream, and it was immediate revenue – not revenue waiting on a claim to be paid.”

Illinois-based family physician Deborah L. Winiger, MD, says she also applied for the Paycheck Protection Program but in the meantime had to reduce staff hours by a third because her patient volume dropped by more than half. She will also encourage staff to pursue temporary positions at a local hospital if the federal funds don’t materialize.

Kelly Shackleton, practice manager at a New York-based internal medicine practice, says she laid off 7 of her 16 staff members (including lab technicians, licensed practical nurses, billers, a referral specialist, and a file clerk) due to a 70% decrease in patient volume.

“I didn’t lay them all off at once,” she says. “I kept them until things were all caught up in each department. I plan to get them all back when the time is right, but I want to be sure to keep the practice afloat so they have a place to return to.” If the Paycheck Protection Program for which she applied comes through, then she will rehire them. She also applied for Medicare advanced payments and increased the practice’s line of credit.
 

Bill properly – and for everything you are still doing

Accurate and complete coding is critical during this time of financial instability, says Maselli. “I keep telling doctors to bill for everything they do,” he says. This includes phone calls between patients and physicians or other qualified healthcare providers (CPT codes 99441-99443). Note that these are time-based codes, requiring a minimum of five minutes of medical discussion.

Remote physiologic monitoring (including monitoring a patient’s oxygen saturation levels using pulse oximetry), virtual check-ins, and online digital evaluation and management services are also covered by Medicare and some commercial payers.

Other good news is that the Centers for Medicare & Medicaid Services added more than 80 additional services that providers can furnish using telehealth, including new patient office visits, home visits, prolonged office visits, smoking and tobacco cessation counseling, annual depression and alcohol screenings, advanced care planning, and much more.

Mongillo, the family practice administrator in Delaware, agrees that physicians need to bill for as many services as possible. At one of the family medicine practices she manages, physicians perform wellness visits, when appropriate, if patients are already coming into the office for another ailment.

Also look for ways to cut costs. For example, Mongillo was able to renegotiate the practice’s telemedicine contract after she received several proposals from other vendors offering three months of complimentary service. Shackleton discontinued provider dictation services to save money.

Physicians need to take a hard look at what’s going on to help them sustain their business through times of uncertainty, says Advisory Board’s Hostetter. “Now is the time to evaluate options and figure out what’s right for your practice,” she adds.

This article first appeared on Medscape.com.

The monoclonal antibody omalizumab, already approved to treat allergic asthma and urticaria, has been shown to improve symptoms of patients who have chronic rhinosinusitis and nasal polyps (CRSwNP), according to recent research released as an abstract from the American Academy of Allergy, Asthma, and Immunology annual meeting. The AAAAI canceled the meeting and provided abstracts and access to presenters for press coverage.

“When you give this drug to patients who have nasal polyposis and concomitant asthma, you are effectively treating both the upper and lower airway disease components,” Jonathan Corren, MD, of the University of California, Los Angeles, said in an interview. “Typically, people with nasal polyp disease have worse nasal disease than people without asthma. In addition, asthma is also generally worse in patients with nasal polyposis,” he added.

Dr. Corren reported results of a subset of patients with corticosteroid-refractory CRSwNP and comorbid asthma enrolled in phase III, placebo-controlled, 24-week, trials of omalizumab, POLYP1 (n = 74) and POLYP2 (n = 77). The analysis excluded patients who were on oral steroids or high-dose steroid inhaler therapy so the effectiveness of omalizumab could be evaluated without interfering factors, Dr. Corren explained. As a result, the study population consisted of patients with mild to moderate asthma. Dr. Corren is also principal investigator of the POLYP1 trial.

The analysis compared changes in Asthma Quality of Life Questionnaire (AQLQ) and sino-nasal outcome test (SNOT-22) measures after 24 weeks of treatment with those seen with placebo.

“With regard to asthma outcomes, we found there was a significant increase in the odds ratio that patients who received omalizumab would achieve a minimal, clinically important improvement in their asthma quality of life,” Dr. Corren said .

The study estimated the odds ratio for minimal clinically important difference in AQLQ at 24 weeks was 3.9 (95% confidence interval, 1.5-9.7; P = .0043), which Dr. Corren called “quite significant.” SNOT-22 scores showed a mean improvement of 23.3 from baseline to week 24, compared with a worsening of 8.4 in placebo (P = .0001).

Omalizumab is approved for treatment of perennial allergies and urticaria. Chronic rhinosinusitis with nasal polyps would be a third indication if the Food and Drug Administration approves it, Dr. Corren noted.

Genentech sponsored the subset analysis. Hoffmann-La Roche, Genentech’s parent company, is sponsor of the POLYP1 and POLYP2 trials. Dr. Corren disclosed financial relationships with Genentech.

SOURCE: Corren J et al. AAAAI, Session 4608, Abstract 813.

The monoclonal antibody omalizumab, already approved to treat allergic asthma and urticaria, has been shown to improve symptoms of patients who have chronic rhinosinusitis and nasal polyps (CRSwNP), according to recent research released as an abstract from the American Academy of Allergy, Asthma, and Immunology annual meeting. The AAAAI canceled the meeting and provided abstracts and access to presenters for press coverage.

“When you give this drug to patients who have nasal polyposis and concomitant asthma, you are effectively treating both the upper and lower airway disease components,” Jonathan Corren, MD, of the University of California, Los Angeles, said in an interview. “Typically, people with nasal polyp disease have worse nasal disease than people without asthma. In addition, asthma is also generally worse in patients with nasal polyposis,” he added.

Dr. Corren reported results of a subset of patients with corticosteroid-refractory CRSwNP and comorbid asthma enrolled in phase III, placebo-controlled, 24-week, trials of omalizumab, POLYP1 (n = 74) and POLYP2 (n = 77). The analysis excluded patients who were on oral steroids or high-dose steroid inhaler therapy so the effectiveness of omalizumab could be evaluated without interfering factors, Dr. Corren explained. As a result, the study population consisted of patients with mild to moderate asthma. Dr. Corren is also principal investigator of the POLYP1 trial.

The analysis compared changes in Asthma Quality of Life Questionnaire (AQLQ) and sino-nasal outcome test (SNOT-22) measures after 24 weeks of treatment with those seen with placebo.

“With regard to asthma outcomes, we found there was a significant increase in the odds ratio that patients who received omalizumab would achieve a minimal, clinically important improvement in their asthma quality of life,” Dr. Corren said .

The study estimated the odds ratio for minimal clinically important difference in AQLQ at 24 weeks was 3.9 (95% confidence interval, 1.5-9.7; P = .0043), which Dr. Corren called “quite significant.” SNOT-22 scores showed a mean improvement of 23.3 from baseline to week 24, compared with a worsening of 8.4 in placebo (P = .0001).

Omalizumab is approved for treatment of perennial allergies and urticaria. Chronic rhinosinusitis with nasal polyps would be a third indication if the Food and Drug Administration approves it, Dr. Corren noted.

Genentech sponsored the subset analysis. Hoffmann-La Roche, Genentech’s parent company, is sponsor of the POLYP1 and POLYP2 trials. Dr. Corren disclosed financial relationships with Genentech.

SOURCE: Corren J et al. AAAAI, Session 4608, Abstract 813.

The monoclonal antibody omalizumab, already approved to treat allergic asthma and urticaria, has been shown to improve symptoms of patients who have chronic rhinosinusitis and nasal polyps (CRSwNP), according to recent research released as an abstract from the American Academy of Allergy, Asthma, and Immunology annual meeting. The AAAAI canceled the meeting and provided abstracts and access to presenters for press coverage.

“When you give this drug to patients who have nasal polyposis and concomitant asthma, you are effectively treating both the upper and lower airway disease components,” Jonathan Corren, MD, of the University of California, Los Angeles, said in an interview. “Typically, people with nasal polyp disease have worse nasal disease than people without asthma. In addition, asthma is also generally worse in patients with nasal polyposis,” he added.

Dr. Corren reported results of a subset of patients with corticosteroid-refractory CRSwNP and comorbid asthma enrolled in phase III, placebo-controlled, 24-week, trials of omalizumab, POLYP1 (n = 74) and POLYP2 (n = 77). The analysis excluded patients who were on oral steroids or high-dose steroid inhaler therapy so the effectiveness of omalizumab could be evaluated without interfering factors, Dr. Corren explained. As a result, the study population consisted of patients with mild to moderate asthma. Dr. Corren is also principal investigator of the POLYP1 trial.

The analysis compared changes in Asthma Quality of Life Questionnaire (AQLQ) and sino-nasal outcome test (SNOT-22) measures after 24 weeks of treatment with those seen with placebo.

“With regard to asthma outcomes, we found there was a significant increase in the odds ratio that patients who received omalizumab would achieve a minimal, clinically important improvement in their asthma quality of life,” Dr. Corren said .

The study estimated the odds ratio for minimal clinically important difference in AQLQ at 24 weeks was 3.9 (95% confidence interval, 1.5-9.7; P = .0043), which Dr. Corren called “quite significant.” SNOT-22 scores showed a mean improvement of 23.3 from baseline to week 24, compared with a worsening of 8.4 in placebo (P = .0001).

Omalizumab is approved for treatment of perennial allergies and urticaria. Chronic rhinosinusitis with nasal polyps would be a third indication if the Food and Drug Administration approves it, Dr. Corren noted.

Genentech sponsored the subset analysis. Hoffmann-La Roche, Genentech’s parent company, is sponsor of the POLYP1 and POLYP2 trials. Dr. Corren disclosed financial relationships with Genentech.

SOURCE: Corren J et al. AAAAI, Session 4608, Abstract 813.

As a department chief managing during this crisis, everyone greets me sympathetically: “This must be so stressful for you! Are you doing OK?” “Um, I’m great,” I answer contritely. Yes, this is hard, yet I feel fine. But why? Shouldn’t I be fretting the damage done by the COVID cyclone? Our operations are smashed and our staff scrambled, my family and friends are out of work; these are difficult times. But a harmful effect on my health or yours is not inevitable. There are things we can do to inoculate ourselves.

karandaev/iStock/Getty Images

No doubt, exercise (if you can find weights!), eating well, sleeping, and meditating help, but they are secondary. None of these protect much if you still believe stress is killing you. You must first reframe what is happening. Health psychologist Kelly McGonigal, PhD, from Stanford (Calif.) University, is a world expert on this topic. If you’ve not seen her TED talk about stress, then watch it now. She teaches how stress is indeed harmful to your health – but only if you believe it to be so. Many studies have borne this out. One showed that people who reported high stress in the previous year were 43% more likely to die than those who did not. But that risk held only when they believed stress was harmful to them. Those who did not think that stress was harmful not only fared better but also had the lowest likelihood of death, lower even than those who reported little stress! So it wasn’t the stress that mattered, it was the physiologic response to it. And that you can control.

Changing your beliefs is no easy feat. There is work to be done, Dr. McGonigal would argue. You must not only reframe our stress as healthful, but also act in ways to make this true. This is easier for us as physicians. First, we understand better than most that difficulty is a normal part of life. We have countless stories of hardship, tragedy, pain and suffering from the work we do. The pandemic may be extraordinary in breadth, but not in depth. We’ve seen worse happen to patients. Second, we have firsthand experience that suffering ends and often leads to strength and resilience. Even in our own lives, it was by traveling through the extraordinary stress of medical school and residency that we arrived here. That trying period in your life forged the strength, courage, which serves you today. It also made you more compassionate. Here lies the biggest take-away for COVID survival.

Cortisol increases when we are under duress. So does oxytocin. The former gets most of the press, the latter is more interesting. That oxytocin release during stress conferred survival benefits to us as a species: When a threat arrived, we not only ran, but also grabbed the kids, too! Oxytocin is the “tend and befriend” compliment to cortisol’s “fight or flight.” Focusing on this priming to strengthen social ties, listen, spend (Zoom) time together, and provide emotional support is key to our recovery. Even small acts of giving for our staff, friends, family, and strangers can significantly shift consequences of this stress from harmful to beneficial.

Last year, my uncle died in a tragic accident. My aunt, who is alone, is now also isolated. She’s lost her partner, her guardian, and she is afraid. Rather than succumb to the stress, she imagined something she could do to wrest some control. Last week, she filled her minivan with pink and yellow tulips bunched in bouquets and tied with handwritten notes of encouragement. She then drove up and down the streets in her North Attleboro, Mass., neighborhood and left the flowers on doorsteps until her van was empty. She did so to share with them the bit of joy that spring brings, she says, and to encourage people to stay inside!

This is a difficult time for us, and yet even more difficult for others. Perhaps the best we can do is to find ways to bring a bit of joy or comfort to others.


“In some ways suffering ceases to be suffering at the moment it finds a meaning, such as the meaning of a sacrifice.” – Viktor Frankl

Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. He had no relevant disclosures. Dr. Benabio is @Dermdoc on Twitter. Write to him at dermnews@mdedge.com.

As a department chief managing during this crisis, everyone greets me sympathetically: “This must be so stressful for you! Are you doing OK?” “Um, I’m great,” I answer contritely. Yes, this is hard, yet I feel fine. But why? Shouldn’t I be fretting the damage done by the COVID cyclone? Our operations are smashed and our staff scrambled, my family and friends are out of work; these are difficult times. But a harmful effect on my health or yours is not inevitable. There are things we can do to inoculate ourselves.

karandaev/iStock/Getty Images

No doubt, exercise (if you can find weights!), eating well, sleeping, and meditating help, but they are secondary. None of these protect much if you still believe stress is killing you. You must first reframe what is happening. Health psychologist Kelly McGonigal, PhD, from Stanford (Calif.) University, is a world expert on this topic. If you’ve not seen her TED talk about stress, then watch it now. She teaches how stress is indeed harmful to your health – but only if you believe it to be so. Many studies have borne this out. One showed that people who reported high stress in the previous year were 43% more likely to die than those who did not. But that risk held only when they believed stress was harmful to them. Those who did not think that stress was harmful not only fared better but also had the lowest likelihood of death, lower even than those who reported little stress! So it wasn’t the stress that mattered, it was the physiologic response to it. And that you can control.

Changing your beliefs is no easy feat. There is work to be done, Dr. McGonigal would argue. You must not only reframe our stress as healthful, but also act in ways to make this true. This is easier for us as physicians. First, we understand better than most that difficulty is a normal part of life. We have countless stories of hardship, tragedy, pain and suffering from the work we do. The pandemic may be extraordinary in breadth, but not in depth. We’ve seen worse happen to patients. Second, we have firsthand experience that suffering ends and often leads to strength and resilience. Even in our own lives, it was by traveling through the extraordinary stress of medical school and residency that we arrived here. That trying period in your life forged the strength, courage, which serves you today. It also made you more compassionate. Here lies the biggest take-away for COVID survival.

Cortisol increases when we are under duress. So does oxytocin. The former gets most of the press, the latter is more interesting. That oxytocin release during stress conferred survival benefits to us as a species: When a threat arrived, we not only ran, but also grabbed the kids, too! Oxytocin is the “tend and befriend” compliment to cortisol’s “fight or flight.” Focusing on this priming to strengthen social ties, listen, spend (Zoom) time together, and provide emotional support is key to our recovery. Even small acts of giving for our staff, friends, family, and strangers can significantly shift consequences of this stress from harmful to beneficial.

Last year, my uncle died in a tragic accident. My aunt, who is alone, is now also isolated. She’s lost her partner, her guardian, and she is afraid. Rather than succumb to the stress, she imagined something she could do to wrest some control. Last week, she filled her minivan with pink and yellow tulips bunched in bouquets and tied with handwritten notes of encouragement. She then drove up and down the streets in her North Attleboro, Mass., neighborhood and left the flowers on doorsteps until her van was empty. She did so to share with them the bit of joy that spring brings, she says, and to encourage people to stay inside!

This is a difficult time for us, and yet even more difficult for others. Perhaps the best we can do is to find ways to bring a bit of joy or comfort to others.


“In some ways suffering ceases to be suffering at the moment it finds a meaning, such as the meaning of a sacrifice.” – Viktor Frankl

Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. He had no relevant disclosures. Dr. Benabio is @Dermdoc on Twitter. Write to him at dermnews@mdedge.com.

As a department chief managing during this crisis, everyone greets me sympathetically: “This must be so stressful for you! Are you doing OK?” “Um, I’m great,” I answer contritely. Yes, this is hard, yet I feel fine. But why? Shouldn’t I be fretting the damage done by the COVID cyclone? Our operations are smashed and our staff scrambled, my family and friends are out of work; these are difficult times. But a harmful effect on my health or yours is not inevitable. There are things we can do to inoculate ourselves.

karandaev/iStock/Getty Images

No doubt, exercise (if you can find weights!), eating well, sleeping, and meditating help, but they are secondary. None of these protect much if you still believe stress is killing you. You must first reframe what is happening. Health psychologist Kelly McGonigal, PhD, from Stanford (Calif.) University, is a world expert on this topic. If you’ve not seen her TED talk about stress, then watch it now. She teaches how stress is indeed harmful to your health – but only if you believe it to be so. Many studies have borne this out. One showed that people who reported high stress in the previous year were 43% more likely to die than those who did not. But that risk held only when they believed stress was harmful to them. Those who did not think that stress was harmful not only fared better but also had the lowest likelihood of death, lower even than those who reported little stress! So it wasn’t the stress that mattered, it was the physiologic response to it. And that you can control.

Changing your beliefs is no easy feat. There is work to be done, Dr. McGonigal would argue. You must not only reframe our stress as healthful, but also act in ways to make this true. This is easier for us as physicians. First, we understand better than most that difficulty is a normal part of life. We have countless stories of hardship, tragedy, pain and suffering from the work we do. The pandemic may be extraordinary in breadth, but not in depth. We’ve seen worse happen to patients. Second, we have firsthand experience that suffering ends and often leads to strength and resilience. Even in our own lives, it was by traveling through the extraordinary stress of medical school and residency that we arrived here. That trying period in your life forged the strength, courage, which serves you today. It also made you more compassionate. Here lies the biggest take-away for COVID survival.

Cortisol increases when we are under duress. So does oxytocin. The former gets most of the press, the latter is more interesting. That oxytocin release during stress conferred survival benefits to us as a species: When a threat arrived, we not only ran, but also grabbed the kids, too! Oxytocin is the “tend and befriend” compliment to cortisol’s “fight or flight.” Focusing on this priming to strengthen social ties, listen, spend (Zoom) time together, and provide emotional support is key to our recovery. Even small acts of giving for our staff, friends, family, and strangers can significantly shift consequences of this stress from harmful to beneficial.

Last year, my uncle died in a tragic accident. My aunt, who is alone, is now also isolated. She’s lost her partner, her guardian, and she is afraid. Rather than succumb to the stress, she imagined something she could do to wrest some control. Last week, she filled her minivan with pink and yellow tulips bunched in bouquets and tied with handwritten notes of encouragement. She then drove up and down the streets in her North Attleboro, Mass., neighborhood and left the flowers on doorsteps until her van was empty. She did so to share with them the bit of joy that spring brings, she says, and to encourage people to stay inside!

This is a difficult time for us, and yet even more difficult for others. Perhaps the best we can do is to find ways to bring a bit of joy or comfort to others.


“In some ways suffering ceases to be suffering at the moment it finds a meaning, such as the meaning of a sacrifice.” – Viktor Frankl

Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. He had no relevant disclosures. Dr. Benabio is @Dermdoc on Twitter. Write to him at dermnews@mdedge.com.

The Food and Drug Administration has authorized the first diagnostic test with a home collection option for COVID-19, a reissue of the emergency use authorization allowing for testing of samples self-collected by patients at home with the Pixel by LabCorp COVID-19 RT-PCR Test.

Wikimedia Commons/FitzColinGerald/ Creative Commons License

The reissued authorization allows for testing of a sample taken from the nose by way of a self-collection kit that contains nasal swabs and saline, according to the FDA press release. After self-swabbing, users should send the samples in an insulated package to a LabCorp laboratory for testing. LabCorp intends to make the Pixel test available to consumers in most states, accessible through doctors’ orders.

The Pixel test includes a specific Q-tip–style cotton swab for patients to use to collect their samples, the FDA noted. Because of concerns with sterility and cross-reactivity caused by inherent genetic material in cotton swabs, generic cotton swabs should not be used as a substitute. The FDA will work with test developers to determine if generic cotton swabs can be used safely and effectively with other tests.

“Throughout this pandemic we have been facilitating test development to ensure patients’ access to accurate diagnostics, which includes supporting the development of reliable and accurate at-home sample collection options. ... [The FDA] worked with LabCorp to ensure the data demonstrated from at-home patient sample collection is as safe and accurate as sample collection at a doctor’s office, hospital, or other testing site. With this action, there is now a convenient and reliable option for patient sample collection from the comfort and safety of their home,” FDA Commissioner Stephen M. Hahn, MD, said in the press release.

lfranki@mdedge.com

The Food and Drug Administration has authorized the first diagnostic test with a home collection option for COVID-19, a reissue of the emergency use authorization allowing for testing of samples self-collected by patients at home with the Pixel by LabCorp COVID-19 RT-PCR Test.

Wikimedia Commons/FitzColinGerald/ Creative Commons License

The reissued authorization allows for testing of a sample taken from the nose by way of a self-collection kit that contains nasal swabs and saline, according to the FDA press release. After self-swabbing, users should send the samples in an insulated package to a LabCorp laboratory for testing. LabCorp intends to make the Pixel test available to consumers in most states, accessible through doctors’ orders.

The Pixel test includes a specific Q-tip–style cotton swab for patients to use to collect their samples, the FDA noted. Because of concerns with sterility and cross-reactivity caused by inherent genetic material in cotton swabs, generic cotton swabs should not be used as a substitute. The FDA will work with test developers to determine if generic cotton swabs can be used safely and effectively with other tests.

“Throughout this pandemic we have been facilitating test development to ensure patients’ access to accurate diagnostics, which includes supporting the development of reliable and accurate at-home sample collection options. ... [The FDA] worked with LabCorp to ensure the data demonstrated from at-home patient sample collection is as safe and accurate as sample collection at a doctor’s office, hospital, or other testing site. With this action, there is now a convenient and reliable option for patient sample collection from the comfort and safety of their home,” FDA Commissioner Stephen M. Hahn, MD, said in the press release.

lfranki@mdedge.com

The Food and Drug Administration has authorized the first diagnostic test with a home collection option for COVID-19, a reissue of the emergency use authorization allowing for testing of samples self-collected by patients at home with the Pixel by LabCorp COVID-19 RT-PCR Test.

Wikimedia Commons/FitzColinGerald/ Creative Commons License

The reissued authorization allows for testing of a sample taken from the nose by way of a self-collection kit that contains nasal swabs and saline, according to the FDA press release. After self-swabbing, users should send the samples in an insulated package to a LabCorp laboratory for testing. LabCorp intends to make the Pixel test available to consumers in most states, accessible through doctors’ orders.

The Pixel test includes a specific Q-tip–style cotton swab for patients to use to collect their samples, the FDA noted. Because of concerns with sterility and cross-reactivity caused by inherent genetic material in cotton swabs, generic cotton swabs should not be used as a substitute. The FDA will work with test developers to determine if generic cotton swabs can be used safely and effectively with other tests.

“Throughout this pandemic we have been facilitating test development to ensure patients’ access to accurate diagnostics, which includes supporting the development of reliable and accurate at-home sample collection options. ... [The FDA] worked with LabCorp to ensure the data demonstrated from at-home patient sample collection is as safe and accurate as sample collection at a doctor’s office, hospital, or other testing site. With this action, there is now a convenient and reliable option for patient sample collection from the comfort and safety of their home,” FDA Commissioner Stephen M. Hahn, MD, said in the press release.

lfranki@mdedge.com

Patients with a mild traumatic brain injury (mTBI) who are exposed to blue light experience less depression and fewer cognitive and other concussion-related symptoms than those exposed to a placebo light, a new study has found. Exposure to blue light in the morning through a special device may be a “critical factor” in resetting the circadian rhythm and helping people who have suffered a concussion, author William D. “Scott” Killgore, MD, professor of psychiatry, psychology, and medical imaging, the University of Arizona College of Medicine, Tucson, told Medscape Medical News.

“This is very new, so I wouldn’t say it’s the treatment of choice, but we should start looking at using this system as a nonpharmacologic way to perhaps help patients recover faster from a concussion,” he said.

The findings were released March 2 ahead of the study’s scheduled presentation at the annual meeting of the American Academy of Neurology. The AAN canceled the meeting and released abstracts and access to presenters for press coverage.

About half of patients with a concussion experience sleep problems, including problems falling asleep, staying asleep, and waking up in the middle of the night, said Dr. Killgore.

Poor sleep interrupts the brain’s repair mechanism. “Sleep is important for cleaning out the neurotoxins that build up in your brain during the day. Sleep also helps build oligodendrocyte precursor cells that provide insulation around nerve cells,” he said.
 

Master clock

Blue light stimulates receptors in the back of the retina that respond only to this wavelength of light, said Dr. Killgore. “It specifically projects to an area in the hypothalamus – essentially the brain’s master clock – that regulates your sleep-wake schedules. So exposure to that bright light essentially resets your circadian rhythm.”

That master clock involves regulating the brain’s production of melatonin. Morning exposure to blue light shifts that production to facilitate sleep at the appropriate time.

The ideal time to be exposed to blue light is from about 8:00 to 11:00 AM. “Timing is critical,” said Dr. Killgore. “If you get light at the wrong time, it will reset your circadian rhythm in the wrong direction.”

Previous research has shown that exposure to blue light leads to improved sleep, which is widely believed to lead to improved mood.

A separate study conducted by Dr. Killgore and colleagues that involved another group of mTBI patients was recently published in Neurobiology of Disease. That study showed that the participants who received blue light experienced a shift in circadian timing of about an hour. “They were going to sleep an hour earlier and waking up an hour earlier,” said Dr. Killgore.

The blue light also appeared to change brain structure and brain function, among other things, he said.

The current study included 35 patients who had suffered an mTBI within the previous 18 months. Most injuries were sports related and occurred while playing football or soccer or riding a bike.

Participants were randomly assigned to use a device fitted with a blue LED light (peak wavelength, 469 nm) or one fitted with an amber-colored LED light. They were instructed to use the device every morning for 30 minutes within 2 hours of waking.

The blue-light group comprised five men and 12 women (mean age, 25.5 years). The amber-light group comprised eight men and 10 women (mean age, 26.3 years).

Researchers told participants only that the study was exploring various aspects of light. “Subjects didn’t know if they were getting a control or active device,” said Dr. Killgore.

Researchers used the Beck Depression Inventory (BDI) to evaluate depression symptoms and the Rivermead Post-Concussion Symptom Questionnaire (RPCSQ). This 16-item questionnaire assesses symptoms in the acute stage as well as those that are more chronic.

After 6 weeks, the blue-light group had lower scores on the BDI compared to the amber-light group (P = .005).

“We found that in the amber-light group, there was essentially no change in terms of depression,” said Dr. Killgore. “But those who got the blue light showed a significant reduction in depressive symptoms, about a 22% decline overall relative to baseline, so a nice drop in overall depression.”

Changes in BDI scores were significantly positively associated with changes in the total chronic symptom score (P = .002) in the blue-light group but not the amber-light group. “Those who got blue light showed a significant reduction in the number of symptoms associated with concussion whereas those who got the amber light stayed the same,” said Dr. Killgore.

There were similar findings for somatic symptoms, such as headache and pain (P = .031), and for cognitive symptoms (P = .014) in the blue-light group.

“These subjects were having fewer problems remembering and paying attention, so their concentration seemed to be improving, at least subjectively,” commented Dr. Killgore.

There was no significant benefit from the blue light for emotional symptoms. “There was a decline, but it wasn’t statistically significant, even though there was a decline in depression,” said Dr. Killgore.

This, he explained, could be due to the small sample size and the greater sensitivity of the BDI for emotional symptoms relative to the RPCSQ. “The BDI has 21 items that are all focused on aspects of depression, whereas the RPCSQ only asks one item for depression and one item for irritability/anger.”

Less daytime sleepiness

The researchers also found a significant improvement in daytime sleepiness. “Subjects were much less sleepy by the end of the study if they got blue light than if they got amber light,” said Dr. Killgore.

Participants wore an actigraphy device that took sleep measurements. Early results indicate that blue-light recipients were getting more sleep by the end of the study.

Researchers are now analyzing additional data to see whether the improvements in depression and post-concussion symptoms are linked to improved sleep. They also gathered data from brain imaging that will be analyzed at a later date.

Dr. Killgore and his colleagues aim to determine what distinguishes people who respond to blue-light therapy from those who don’t. “We want to know what it is that would allow some people to be more responsive than others, so we’re going to be exploring skin color, eye color, genetic factors, and other factors,” he said.

They’re also conducting a study of blue-light therapy in patients with posttraumatic stress disorder, 90% of whom have sleep problems.

“This is quite fascinating,” said Dr. Killgore. “It looks like if you get blue light after your treatment, the treatment sticks better than if you didn’t get the blue light. We think that sleep is probably playing an important role in that.”

Several light devices are available, ranging in price from about $100 to $200.

Commenting on the research, concussion expert Frank Conidi, MD, director of the Florida Center for Headache and Sports Neurology, Port St. Lucie, said the study is interesting from a number of perspectives.

For one thing, it shows that blue-light therapy “provides an inexpensive and minimally invasive way to treat concussion,” he said.

Dr. Conidi said he would recommend blue-light therapy for concussion patients. “I could see neurology practices offering the device to patients as an in-office treatment or to take home for a small fee. I think athletes would be quite receptive to this, as they’re always looking for nonpharmacological ways to treat concussion.”

Dr. Conidi noted that the new results are consistent with other studies that show that decreased depression and improved sleep help with somatic symptoms.

From a research perspective, the study provides a “stepping stone” for larger trials, said Dr. Conidi. He would like to see more studies of acute concussion, such as studies as to whether the therapy shortens the duration of symptoms.

“I would also like to see controlled studies on headache and vestibular symptoms, which are the two most common,” he said.

The study was funded by the US Department of Defense. Killgore and Conidi have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Patients with a mild traumatic brain injury (mTBI) who are exposed to blue light experience less depression and fewer cognitive and other concussion-related symptoms than those exposed to a placebo light, a new study has found. Exposure to blue light in the morning through a special device may be a “critical factor” in resetting the circadian rhythm and helping people who have suffered a concussion, author William D. “Scott” Killgore, MD, professor of psychiatry, psychology, and medical imaging, the University of Arizona College of Medicine, Tucson, told Medscape Medical News.

“This is very new, so I wouldn’t say it’s the treatment of choice, but we should start looking at using this system as a nonpharmacologic way to perhaps help patients recover faster from a concussion,” he said.

The findings were released March 2 ahead of the study’s scheduled presentation at the annual meeting of the American Academy of Neurology. The AAN canceled the meeting and released abstracts and access to presenters for press coverage.

About half of patients with a concussion experience sleep problems, including problems falling asleep, staying asleep, and waking up in the middle of the night, said Dr. Killgore.

Poor sleep interrupts the brain’s repair mechanism. “Sleep is important for cleaning out the neurotoxins that build up in your brain during the day. Sleep also helps build oligodendrocyte precursor cells that provide insulation around nerve cells,” he said.
 

Master clock

Blue light stimulates receptors in the back of the retina that respond only to this wavelength of light, said Dr. Killgore. “It specifically projects to an area in the hypothalamus – essentially the brain’s master clock – that regulates your sleep-wake schedules. So exposure to that bright light essentially resets your circadian rhythm.”

That master clock involves regulating the brain’s production of melatonin. Morning exposure to blue light shifts that production to facilitate sleep at the appropriate time.

The ideal time to be exposed to blue light is from about 8:00 to 11:00 AM. “Timing is critical,” said Dr. Killgore. “If you get light at the wrong time, it will reset your circadian rhythm in the wrong direction.”

Previous research has shown that exposure to blue light leads to improved sleep, which is widely believed to lead to improved mood.

A separate study conducted by Dr. Killgore and colleagues that involved another group of mTBI patients was recently published in Neurobiology of Disease. That study showed that the participants who received blue light experienced a shift in circadian timing of about an hour. “They were going to sleep an hour earlier and waking up an hour earlier,” said Dr. Killgore.

The blue light also appeared to change brain structure and brain function, among other things, he said.

The current study included 35 patients who had suffered an mTBI within the previous 18 months. Most injuries were sports related and occurred while playing football or soccer or riding a bike.

Participants were randomly assigned to use a device fitted with a blue LED light (peak wavelength, 469 nm) or one fitted with an amber-colored LED light. They were instructed to use the device every morning for 30 minutes within 2 hours of waking.

The blue-light group comprised five men and 12 women (mean age, 25.5 years). The amber-light group comprised eight men and 10 women (mean age, 26.3 years).

Researchers told participants only that the study was exploring various aspects of light. “Subjects didn’t know if they were getting a control or active device,” said Dr. Killgore.

Researchers used the Beck Depression Inventory (BDI) to evaluate depression symptoms and the Rivermead Post-Concussion Symptom Questionnaire (RPCSQ). This 16-item questionnaire assesses symptoms in the acute stage as well as those that are more chronic.

After 6 weeks, the blue-light group had lower scores on the BDI compared to the amber-light group (P = .005).

“We found that in the amber-light group, there was essentially no change in terms of depression,” said Dr. Killgore. “But those who got the blue light showed a significant reduction in depressive symptoms, about a 22% decline overall relative to baseline, so a nice drop in overall depression.”

Changes in BDI scores were significantly positively associated with changes in the total chronic symptom score (P = .002) in the blue-light group but not the amber-light group. “Those who got blue light showed a significant reduction in the number of symptoms associated with concussion whereas those who got the amber light stayed the same,” said Dr. Killgore.

There were similar findings for somatic symptoms, such as headache and pain (P = .031), and for cognitive symptoms (P = .014) in the blue-light group.

“These subjects were having fewer problems remembering and paying attention, so their concentration seemed to be improving, at least subjectively,” commented Dr. Killgore.

There was no significant benefit from the blue light for emotional symptoms. “There was a decline, but it wasn’t statistically significant, even though there was a decline in depression,” said Dr. Killgore.

This, he explained, could be due to the small sample size and the greater sensitivity of the BDI for emotional symptoms relative to the RPCSQ. “The BDI has 21 items that are all focused on aspects of depression, whereas the RPCSQ only asks one item for depression and one item for irritability/anger.”

Less daytime sleepiness

The researchers also found a significant improvement in daytime sleepiness. “Subjects were much less sleepy by the end of the study if they got blue light than if they got amber light,” said Dr. Killgore.

Participants wore an actigraphy device that took sleep measurements. Early results indicate that blue-light recipients were getting more sleep by the end of the study.

Researchers are now analyzing additional data to see whether the improvements in depression and post-concussion symptoms are linked to improved sleep. They also gathered data from brain imaging that will be analyzed at a later date.

Dr. Killgore and his colleagues aim to determine what distinguishes people who respond to blue-light therapy from those who don’t. “We want to know what it is that would allow some people to be more responsive than others, so we’re going to be exploring skin color, eye color, genetic factors, and other factors,” he said.

They’re also conducting a study of blue-light therapy in patients with posttraumatic stress disorder, 90% of whom have sleep problems.

“This is quite fascinating,” said Dr. Killgore. “It looks like if you get blue light after your treatment, the treatment sticks better than if you didn’t get the blue light. We think that sleep is probably playing an important role in that.”

Several light devices are available, ranging in price from about $100 to $200.

Commenting on the research, concussion expert Frank Conidi, MD, director of the Florida Center for Headache and Sports Neurology, Port St. Lucie, said the study is interesting from a number of perspectives.

For one thing, it shows that blue-light therapy “provides an inexpensive and minimally invasive way to treat concussion,” he said.

Dr. Conidi said he would recommend blue-light therapy for concussion patients. “I could see neurology practices offering the device to patients as an in-office treatment or to take home for a small fee. I think athletes would be quite receptive to this, as they’re always looking for nonpharmacological ways to treat concussion.”

Dr. Conidi noted that the new results are consistent with other studies that show that decreased depression and improved sleep help with somatic symptoms.

From a research perspective, the study provides a “stepping stone” for larger trials, said Dr. Conidi. He would like to see more studies of acute concussion, such as studies as to whether the therapy shortens the duration of symptoms.

“I would also like to see controlled studies on headache and vestibular symptoms, which are the two most common,” he said.

The study was funded by the US Department of Defense. Killgore and Conidi have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Patients with a mild traumatic brain injury (mTBI) who are exposed to blue light experience less depression and fewer cognitive and other concussion-related symptoms than those exposed to a placebo light, a new study has found. Exposure to blue light in the morning through a special device may be a “critical factor” in resetting the circadian rhythm and helping people who have suffered a concussion, author William D. “Scott” Killgore, MD, professor of psychiatry, psychology, and medical imaging, the University of Arizona College of Medicine, Tucson, told Medscape Medical News.

“This is very new, so I wouldn’t say it’s the treatment of choice, but we should start looking at using this system as a nonpharmacologic way to perhaps help patients recover faster from a concussion,” he said.

The findings were released March 2 ahead of the study’s scheduled presentation at the annual meeting of the American Academy of Neurology. The AAN canceled the meeting and released abstracts and access to presenters for press coverage.

About half of patients with a concussion experience sleep problems, including problems falling asleep, staying asleep, and waking up in the middle of the night, said Dr. Killgore.

Poor sleep interrupts the brain’s repair mechanism. “Sleep is important for cleaning out the neurotoxins that build up in your brain during the day. Sleep also helps build oligodendrocyte precursor cells that provide insulation around nerve cells,” he said.
 

Master clock

Blue light stimulates receptors in the back of the retina that respond only to this wavelength of light, said Dr. Killgore. “It specifically projects to an area in the hypothalamus – essentially the brain’s master clock – that regulates your sleep-wake schedules. So exposure to that bright light essentially resets your circadian rhythm.”

That master clock involves regulating the brain’s production of melatonin. Morning exposure to blue light shifts that production to facilitate sleep at the appropriate time.

The ideal time to be exposed to blue light is from about 8:00 to 11:00 AM. “Timing is critical,” said Dr. Killgore. “If you get light at the wrong time, it will reset your circadian rhythm in the wrong direction.”

Previous research has shown that exposure to blue light leads to improved sleep, which is widely believed to lead to improved mood.

A separate study conducted by Dr. Killgore and colleagues that involved another group of mTBI patients was recently published in Neurobiology of Disease. That study showed that the participants who received blue light experienced a shift in circadian timing of about an hour. “They were going to sleep an hour earlier and waking up an hour earlier,” said Dr. Killgore.

The blue light also appeared to change brain structure and brain function, among other things, he said.

The current study included 35 patients who had suffered an mTBI within the previous 18 months. Most injuries were sports related and occurred while playing football or soccer or riding a bike.

Participants were randomly assigned to use a device fitted with a blue LED light (peak wavelength, 469 nm) or one fitted with an amber-colored LED light. They were instructed to use the device every morning for 30 minutes within 2 hours of waking.

The blue-light group comprised five men and 12 women (mean age, 25.5 years). The amber-light group comprised eight men and 10 women (mean age, 26.3 years).

Researchers told participants only that the study was exploring various aspects of light. “Subjects didn’t know if they were getting a control or active device,” said Dr. Killgore.

Researchers used the Beck Depression Inventory (BDI) to evaluate depression symptoms and the Rivermead Post-Concussion Symptom Questionnaire (RPCSQ). This 16-item questionnaire assesses symptoms in the acute stage as well as those that are more chronic.

After 6 weeks, the blue-light group had lower scores on the BDI compared to the amber-light group (P = .005).

“We found that in the amber-light group, there was essentially no change in terms of depression,” said Dr. Killgore. “But those who got the blue light showed a significant reduction in depressive symptoms, about a 22% decline overall relative to baseline, so a nice drop in overall depression.”

Changes in BDI scores were significantly positively associated with changes in the total chronic symptom score (P = .002) in the blue-light group but not the amber-light group. “Those who got blue light showed a significant reduction in the number of symptoms associated with concussion whereas those who got the amber light stayed the same,” said Dr. Killgore.

There were similar findings for somatic symptoms, such as headache and pain (P = .031), and for cognitive symptoms (P = .014) in the blue-light group.

“These subjects were having fewer problems remembering and paying attention, so their concentration seemed to be improving, at least subjectively,” commented Dr. Killgore.

There was no significant benefit from the blue light for emotional symptoms. “There was a decline, but it wasn’t statistically significant, even though there was a decline in depression,” said Dr. Killgore.

This, he explained, could be due to the small sample size and the greater sensitivity of the BDI for emotional symptoms relative to the RPCSQ. “The BDI has 21 items that are all focused on aspects of depression, whereas the RPCSQ only asks one item for depression and one item for irritability/anger.”

Less daytime sleepiness

The researchers also found a significant improvement in daytime sleepiness. “Subjects were much less sleepy by the end of the study if they got blue light than if they got amber light,” said Dr. Killgore.

Participants wore an actigraphy device that took sleep measurements. Early results indicate that blue-light recipients were getting more sleep by the end of the study.

Researchers are now analyzing additional data to see whether the improvements in depression and post-concussion symptoms are linked to improved sleep. They also gathered data from brain imaging that will be analyzed at a later date.

Dr. Killgore and his colleagues aim to determine what distinguishes people who respond to blue-light therapy from those who don’t. “We want to know what it is that would allow some people to be more responsive than others, so we’re going to be exploring skin color, eye color, genetic factors, and other factors,” he said.

They’re also conducting a study of blue-light therapy in patients with posttraumatic stress disorder, 90% of whom have sleep problems.

“This is quite fascinating,” said Dr. Killgore. “It looks like if you get blue light after your treatment, the treatment sticks better than if you didn’t get the blue light. We think that sleep is probably playing an important role in that.”

Several light devices are available, ranging in price from about $100 to $200.

Commenting on the research, concussion expert Frank Conidi, MD, director of the Florida Center for Headache and Sports Neurology, Port St. Lucie, said the study is interesting from a number of perspectives.

For one thing, it shows that blue-light therapy “provides an inexpensive and minimally invasive way to treat concussion,” he said.

Dr. Conidi said he would recommend blue-light therapy for concussion patients. “I could see neurology practices offering the device to patients as an in-office treatment or to take home for a small fee. I think athletes would be quite receptive to this, as they’re always looking for nonpharmacological ways to treat concussion.”

Dr. Conidi noted that the new results are consistent with other studies that show that decreased depression and improved sleep help with somatic symptoms.

From a research perspective, the study provides a “stepping stone” for larger trials, said Dr. Conidi. He would like to see more studies of acute concussion, such as studies as to whether the therapy shortens the duration of symptoms.

“I would also like to see controlled studies on headache and vestibular symptoms, which are the two most common,” he said.

The study was funded by the US Department of Defense. Killgore and Conidi have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

With health care systems becoming increasingly stretched as the COVID-19 pandemic sweeps the globe, the European Society for Medical Oncology (ESMO) has produced practical recommendations for prioritizing the management of cancer patients, including those with gynecologic cancers.

ESMO’s guidelines for cervical, endometrial, and epithelial ovarian cancer delineate which patients should be prioritized for treatment in the face of reduced resources and despite the risk of SARS-CoV-2 infection.

“Many European countries have already sorted their own guidelines, either nationally or through their own societies,” said Jonathan Ledermann, MD, a professor of medical oncology at the University College London Cancer Institute who was involved in developing ESMO’s recommendations for gynecologic cancers.

Dr. Ledermann noted that the British Gynaecological Cancer Society, for example, has published guidance on COVID-19 that reflects U.K. practice.

“ESMO obviously feels a responsibility, from the European perspective, to give some guidance to their membership about the COVID-19 situation in the same way that they would put out guidelines if a new drug became available,” Dr. Ledermann said.
 

Prioritizing care

All of the ESMO COVID-19 guidelines group cancer patients into high-, medium-, or low-priority categories to ensure that patients who may need the most care will be seen first as hospital services become affected by the pandemic.

Those in the high-priority category are patients whose condition is either immediately life-threatening or clinically unstable or who may benefit greatly from intervention. Those in the low-priority group are patients who may be stable enough to have treatment delayed while the COVID-19 pandemic is ongoing or for whom the benefit of the intervention is low, compared with the risks of SARS-CoV-2 infection.

Those in the medium-priority group are patients whose treatment is noncritical, but for whom delaying treatment for more than 6 weeks could potentially impact the overall outcome or care of the patient.

For all gynecologic cancers covered, the guidelines stress that decisions made by the multidisciplinary team need to be documented, taking the patient’s condition into account, assessing who may be the most vulnerable, and considering the available resources.
 

High-priority visits

Examples of patients with cervical cancer who are a high priority for outpatient visits, according to the guidelines, include patients who have acute abdominal symptoms, renal obstruction, or complications after surgery or radiotherapy. Persistent and severe symptomatic pelvic or vaginal bleeding is another reason to be categorized as high priority for an outpatient visit, alongside anuria or symptoms of deep vein thrombosis.

New patients with histologically confirmed cervical changes should also be seen as a high priority to stage their cancer, but the guidelines stress that any blood tests and imaging should be done as close to the patient’s home as possible.

Similar recommendations are made for women with endometrial cancer, with those who have potentially unstable symptoms, severe bleeding from their tumors, and signs of venous thromboembolism or anuria being at the highest priority for outpatient visits.

Women with potentially unstable epithelial ovarian cancer – who have acute abdominal pain, intestinal obstruction, or complications after surgery – are also a high priority for an outpatient visit, as are new patients who have symptomatic ascites, pleural effusion, or intestinal obstruction.
 

Applying guidelines in practice

Knowing that ESMO and other organizations have carefully considered the management of cancer patients specifically in relation to COVID-19 could offer oncologists “a feeling of support and some security when they make difficult decisions,” Dr. Ledermann said.

“With all guidelines, particularly in this sort of situation, we have to be very careful in terms of their interpretation, because what fits one country may not fit another, and what fits one hospital may not necessarily fit another. So they should be taken as guidance rather than prescriptive documents,” Dr. Ledermann said.

As vice president of the European Society for Gynecologic Oncology, Dr. Ledermann noted that ESGO has taken a slightly different approach than ESMO. ESGO decided to collect and post links to existing COVID-19 resources on its website rather than create its own specific recommendations.

ESGO is also producing an expert webinar series, which has, so far, covered the management of ovarian and uterine cancers, giving clinicians the chance to learn from those who have experienced dramatic changes to their services during the COVID-19 pandemic.

Dr. Ledermann has no conflicts of interest.

With health care systems becoming increasingly stretched as the COVID-19 pandemic sweeps the globe, the European Society for Medical Oncology (ESMO) has produced practical recommendations for prioritizing the management of cancer patients, including those with gynecologic cancers.

ESMO’s guidelines for cervical, endometrial, and epithelial ovarian cancer delineate which patients should be prioritized for treatment in the face of reduced resources and despite the risk of SARS-CoV-2 infection.

“Many European countries have already sorted their own guidelines, either nationally or through their own societies,” said Jonathan Ledermann, MD, a professor of medical oncology at the University College London Cancer Institute who was involved in developing ESMO’s recommendations for gynecologic cancers.

Dr. Ledermann noted that the British Gynaecological Cancer Society, for example, has published guidance on COVID-19 that reflects U.K. practice.

“ESMO obviously feels a responsibility, from the European perspective, to give some guidance to their membership about the COVID-19 situation in the same way that they would put out guidelines if a new drug became available,” Dr. Ledermann said.
 

Prioritizing care

All of the ESMO COVID-19 guidelines group cancer patients into high-, medium-, or low-priority categories to ensure that patients who may need the most care will be seen first as hospital services become affected by the pandemic.

Those in the high-priority category are patients whose condition is either immediately life-threatening or clinically unstable or who may benefit greatly from intervention. Those in the low-priority group are patients who may be stable enough to have treatment delayed while the COVID-19 pandemic is ongoing or for whom the benefit of the intervention is low, compared with the risks of SARS-CoV-2 infection.

Those in the medium-priority group are patients whose treatment is noncritical, but for whom delaying treatment for more than 6 weeks could potentially impact the overall outcome or care of the patient.

For all gynecologic cancers covered, the guidelines stress that decisions made by the multidisciplinary team need to be documented, taking the patient’s condition into account, assessing who may be the most vulnerable, and considering the available resources.
 

High-priority visits

Examples of patients with cervical cancer who are a high priority for outpatient visits, according to the guidelines, include patients who have acute abdominal symptoms, renal obstruction, or complications after surgery or radiotherapy. Persistent and severe symptomatic pelvic or vaginal bleeding is another reason to be categorized as high priority for an outpatient visit, alongside anuria or symptoms of deep vein thrombosis.

New patients with histologically confirmed cervical changes should also be seen as a high priority to stage their cancer, but the guidelines stress that any blood tests and imaging should be done as close to the patient’s home as possible.

Similar recommendations are made for women with endometrial cancer, with those who have potentially unstable symptoms, severe bleeding from their tumors, and signs of venous thromboembolism or anuria being at the highest priority for outpatient visits.

Women with potentially unstable epithelial ovarian cancer – who have acute abdominal pain, intestinal obstruction, or complications after surgery – are also a high priority for an outpatient visit, as are new patients who have symptomatic ascites, pleural effusion, or intestinal obstruction.
 

Applying guidelines in practice

Knowing that ESMO and other organizations have carefully considered the management of cancer patients specifically in relation to COVID-19 could offer oncologists “a feeling of support and some security when they make difficult decisions,” Dr. Ledermann said.

“With all guidelines, particularly in this sort of situation, we have to be very careful in terms of their interpretation, because what fits one country may not fit another, and what fits one hospital may not necessarily fit another. So they should be taken as guidance rather than prescriptive documents,” Dr. Ledermann said.

As vice president of the European Society for Gynecologic Oncology, Dr. Ledermann noted that ESGO has taken a slightly different approach than ESMO. ESGO decided to collect and post links to existing COVID-19 resources on its website rather than create its own specific recommendations.

ESGO is also producing an expert webinar series, which has, so far, covered the management of ovarian and uterine cancers, giving clinicians the chance to learn from those who have experienced dramatic changes to their services during the COVID-19 pandemic.

Dr. Ledermann has no conflicts of interest.

With health care systems becoming increasingly stretched as the COVID-19 pandemic sweeps the globe, the European Society for Medical Oncology (ESMO) has produced practical recommendations for prioritizing the management of cancer patients, including those with gynecologic cancers.

ESMO’s guidelines for cervical, endometrial, and epithelial ovarian cancer delineate which patients should be prioritized for treatment in the face of reduced resources and despite the risk of SARS-CoV-2 infection.

“Many European countries have already sorted their own guidelines, either nationally or through their own societies,” said Jonathan Ledermann, MD, a professor of medical oncology at the University College London Cancer Institute who was involved in developing ESMO’s recommendations for gynecologic cancers.

Dr. Ledermann noted that the British Gynaecological Cancer Society, for example, has published guidance on COVID-19 that reflects U.K. practice.

“ESMO obviously feels a responsibility, from the European perspective, to give some guidance to their membership about the COVID-19 situation in the same way that they would put out guidelines if a new drug became available,” Dr. Ledermann said.
 

Prioritizing care

All of the ESMO COVID-19 guidelines group cancer patients into high-, medium-, or low-priority categories to ensure that patients who may need the most care will be seen first as hospital services become affected by the pandemic.

Those in the high-priority category are patients whose condition is either immediately life-threatening or clinically unstable or who may benefit greatly from intervention. Those in the low-priority group are patients who may be stable enough to have treatment delayed while the COVID-19 pandemic is ongoing or for whom the benefit of the intervention is low, compared with the risks of SARS-CoV-2 infection.

Those in the medium-priority group are patients whose treatment is noncritical, but for whom delaying treatment for more than 6 weeks could potentially impact the overall outcome or care of the patient.

For all gynecologic cancers covered, the guidelines stress that decisions made by the multidisciplinary team need to be documented, taking the patient’s condition into account, assessing who may be the most vulnerable, and considering the available resources.
 

High-priority visits

Examples of patients with cervical cancer who are a high priority for outpatient visits, according to the guidelines, include patients who have acute abdominal symptoms, renal obstruction, or complications after surgery or radiotherapy. Persistent and severe symptomatic pelvic or vaginal bleeding is another reason to be categorized as high priority for an outpatient visit, alongside anuria or symptoms of deep vein thrombosis.

New patients with histologically confirmed cervical changes should also be seen as a high priority to stage their cancer, but the guidelines stress that any blood tests and imaging should be done as close to the patient’s home as possible.

Similar recommendations are made for women with endometrial cancer, with those who have potentially unstable symptoms, severe bleeding from their tumors, and signs of venous thromboembolism or anuria being at the highest priority for outpatient visits.

Women with potentially unstable epithelial ovarian cancer – who have acute abdominal pain, intestinal obstruction, or complications after surgery – are also a high priority for an outpatient visit, as are new patients who have symptomatic ascites, pleural effusion, or intestinal obstruction.
 

Applying guidelines in practice

Knowing that ESMO and other organizations have carefully considered the management of cancer patients specifically in relation to COVID-19 could offer oncologists “a feeling of support and some security when they make difficult decisions,” Dr. Ledermann said.

“With all guidelines, particularly in this sort of situation, we have to be very careful in terms of their interpretation, because what fits one country may not fit another, and what fits one hospital may not necessarily fit another. So they should be taken as guidance rather than prescriptive documents,” Dr. Ledermann said.

As vice president of the European Society for Gynecologic Oncology, Dr. Ledermann noted that ESGO has taken a slightly different approach than ESMO. ESGO decided to collect and post links to existing COVID-19 resources on its website rather than create its own specific recommendations.

ESGO is also producing an expert webinar series, which has, so far, covered the management of ovarian and uterine cancers, giving clinicians the chance to learn from those who have experienced dramatic changes to their services during the COVID-19 pandemic.

Dr. Ledermann has no conflicts of interest.

For more information about upcoming events and award deadlines, please visit http://agau.gastro.org and http://www.gastro.org/research-funding.

UPCOMING EVENTS

May 2-5, 2020
Digestive Disease Week® (DDW)
DDW^® 2020 and all associated events have been canceled. While we are disappointed to miss the science, education and networking that are hallmarks of DDW^®, we must focus on the health and safety of our community. Certainly, this cancellation raises many questions. We have attempted to answer them in this FAQ and remain committed to keeping you informed of new details as they form.

Aug. 14-15, 2020
James W. Freston Single Topic Conference: Gastrointestinal Organoids and Engineered Organ Systems
AGA is actively evaluating developments concerning coronavirus. We expect the 2020 James W. Freston Conference will take place as scheduled and continue to monitor the situation.
Chicago, IL

Aug. 14-16, 2020
2020 Principles of GI for the NP and PA
AGA is actively evaluating developments concerning coronavirus. We expect the 2020 Principles of GI for the NP and PA will take place as scheduled and continue to monitor the situation.
Denver, CO
 

For more information about upcoming events and award deadlines, please visit http://agau.gastro.org and http://www.gastro.org/research-funding.

UPCOMING EVENTS

May 2-5, 2020
Digestive Disease Week® (DDW)
DDW^® 2020 and all associated events have been canceled. While we are disappointed to miss the science, education and networking that are hallmarks of DDW^®, we must focus on the health and safety of our community. Certainly, this cancellation raises many questions. We have attempted to answer them in this FAQ and remain committed to keeping you informed of new details as they form.

Aug. 14-15, 2020
James W. Freston Single Topic Conference: Gastrointestinal Organoids and Engineered Organ Systems
AGA is actively evaluating developments concerning coronavirus. We expect the 2020 James W. Freston Conference will take place as scheduled and continue to monitor the situation.
Chicago, IL

Aug. 14-16, 2020
2020 Principles of GI for the NP and PA
AGA is actively evaluating developments concerning coronavirus. We expect the 2020 Principles of GI for the NP and PA will take place as scheduled and continue to monitor the situation.
Denver, CO
 

For more information about upcoming events and award deadlines, please visit http://agau.gastro.org and http://www.gastro.org/research-funding.

UPCOMING EVENTS

May 2-5, 2020
Digestive Disease Week® (DDW)
DDW^® 2020 and all associated events have been canceled. While we are disappointed to miss the science, education and networking that are hallmarks of DDW^®, we must focus on the health and safety of our community. Certainly, this cancellation raises many questions. We have attempted to answer them in this FAQ and remain committed to keeping you informed of new details as they form.

Aug. 14-15, 2020
James W. Freston Single Topic Conference: Gastrointestinal Organoids and Engineered Organ Systems
AGA is actively evaluating developments concerning coronavirus. We expect the 2020 James W. Freston Conference will take place as scheduled and continue to monitor the situation.
Chicago, IL

Aug. 14-16, 2020
2020 Principles of GI for the NP and PA
AGA is actively evaluating developments concerning coronavirus. We expect the 2020 Principles of GI for the NP and PA will take place as scheduled and continue to monitor the situation.
Denver, CO
 

Post hoc analyses of recent large, clinical outcomes studies of PCSK9 inhibitors have revealed two tantalizing and unexpected potential benefits from these drugs: an ability to substantially reduce the incidence or severity of venous thromboembolism and aortic stenosis.

The evidence also suggests that these effects are linked to the ability of these drugs to reduce blood levels of Lp(a) lipoprotein by roughly a quarter, currently the biggest known effect on Lp(a) levels of any approved medication.

One study ran post hoc analyses of venous thromboembolism (VTE) events in the FOURIER pivotal trial of evolocumab (Repatha), with more than 27,500 randomized patients (N Engl J Med. 2017 May 4; 376[18]:1713-22), and in the ODYSSEY OUTCOMES pivotal trial of alirocumab (Praluent), with nearly 19,000 randomized patients (N Engl J Med. 2018 Nov 29;379[22]:2097-2107). The analyses showed that, with evolocumab treatment, the incidence of VTE events fell by a statistically significant 29%, compared with patients on placebo, while in ODYSSEY OUTCOMES patients treated with alirocumab had a 33% cut in VTE events, compared with placebo-treated patients, a difference that just missed statistical significance (Circulation. 2020 Mar 29. doi: 10.1161/CIRCULATIONAHA.120.046524) in analyses that were not prespecified before these trials started, Nicholas A. Marston, MD, said in a presentation of his research during the joint scientific sessions of the American College of Cardiology and the World Heart Federation, which was presented online this year. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.

A combined analysis of 46,488 patients from both studies showed a 31% cut in VTE events with PCSK9 inhibitor treatment, a highly significant finding using VTE endpoints that were not specifically tallied nor adjudicated but collected as part of the serious adverse event reporting in the two pivotal trials, said Dr. Marston, a cardiologist at Brigham and Women’s Hospital in Boston. This is the first report of a statistically significant link between treatment with PCSK9-inhibiting agents and a reduction in VTE, he added. Researchers from the ODYSSEY OUTCOMES trial had reported a VTE analysis in 2019, and while data from that trial on its own showed a nominal 33% lower VTE rate with alirocumab treatment, it just missed statistical significance.

The VTE effect took about a year on treatment to start to manifest. During the first 12 months of FOURIER, the rate of VTE events among patients in the two treatment arms was virtually identical. But starting during months 13-18 on treatment, the event curves in the two arms began to increasingly diverge, and overall during the period from month 13 to the end of the study treatment with evolocumab was linked with a statistically significant 46% reduction in VTE events, compared with patients who received placebo. The results Dr. Marston reported were also published online (Circulation. 2020 Mar 29. doi: 10.1161/CIRCULATIONAHA.120.046397).

The suggestion that this association may be linked to the impact of PCSK9 inhibitors on Lp(a) came from an additional analysis that Dr. Marston presented, which looked at the link between evolocumab use and a change in VTE event rates, compared with placebo, depending on baseline lipoprotein levels. Evolocumab treatment was associated with a roughly similar, modest, and not statistically significant reduction in VTE events, compared with placebo regardless of whether patients had baseline levels of LDL cholesterol below the median or at or above the median. In contrast, when a similar analysis divided patients based on whether their Lp(a) level at baseline was below, or at or above, the median the results showed no discernible effect of evolocumab treatment, compared with on VTE events in patients with lower baseline Lp(a), but in those with higher levels treatment with evolocumab linked with a 48% cut in VTE events, compared with placebo, a statistically significant difference.

In FOURIER, treatment with evolocumab lowered baseline Lp(a) levels by a median of 27%, compared with placebo, among the 25,096 enrolled patients who had their baseline levels measured. As previously reported, prespecified analysis of FOURIER data also showed that the impact of evolocumab, compared with placebo, on the combined rate of coronary heart disease death, MI, or need for urgent coronary revascularization was enhanced among patients with elevated baseline Lp(a) and moderated in those who entered with lower levels. Among patients who entered FOURIER with Lp(a) levels at or below the median treatment with evolocumab cut the primary endpoint by 7%, compared with placebo, a difference that was not statistically significant. Among patients who began the study with Lp(a) levels above the median, evolocumab treatment cut the primary endpoint by 23%, compared with placebo, a statistically significant effect (Circulation. 2019 Mar 19;139[12]:1483-92).

The aortic stenosis connection

A second study reported in the online scientific sessions (Abstract 914-08) used only FOURIER data, and showed that patients treated with evolocumab had a roughly similar response pattern in their incidence of aortic stenosis (AS) events as they did for VTE events.

During the first year of the study, the incidence of AS events was virtually identical among patients treated with evolocumab and those who received placebo. But after the first 12 months and through the study’s end, patients on evolocumab showed a statistically significant 52% relative reduction in AS events, compared with control patients, said Brian A. Bergmark, MD. For the entire study duration, treatment with evolocumab linked with a 34% relative reduction in AS events, compared with placebo, a difference that did not reach statistical significance, added Dr. Bergmark, an interventional cardiologist also at Brigham and Women’s Hospital. The observed halving in total AS events that linked with evolocumab treatment after the first year of the study included a similar-magnitude reduction specifically in the incidence of aortic valve replacement procedures in the evolocumab-treated patients.

Further analysis of both total AS events and aortic valve replacements in FOURIER patients showed that they occurred at a significantly elevated rate in patients who entered the study with higher baseline Lp(a) levels in a multivariate analysis, but a similar analysis showed no significant association between the incidence of these AS-related events and baseline levels of LDL cholesterol, he said.

The AS analysis carried the same important limitations as the VTE analysis: It ran on a post hoc basis and focused on events that were relatively uncommon and not adjudicated, Dr. Bergmark cautioned. Nonetheless, other investigators saw important potential implications from both the VTE and AS observations, with the huge caveat that they need replication in prospective studies designed to specifically address the validity of these findings.
 

What it could mean

These observed associations between PCSK9 inhibitor treatment and apparent reductions in the rate of both VTE and AS events “represent a tremendous clinical breakthrough,” commented Michelle L. O’Donoghue, MD, a cardiologist at Brigham and Women’s Hospital who is a FOURIER coinvestigator and has led some of the Lp(a) analyses run from that study.

Bruce Jancin/MDedge News

“To date, we have not identified any therapies that slow progression of AS. Other classes of lipid-lowering therapies, such as statins, have been tested and not demonstrated a significant effect,” Dr. O’Donoghue said in an interview.

“For AS, the results are very intriguing. If confirmed, it could be groundbreaking. AS is the most common valve disease in the developed world, and no medical therapy exists. The potential is immense,” commented George Thanassoulis, MD, director of preventive and genomic cardiology at McGill University, Montreal. “Having a medical treatment that could slow AS progression would completely change the disease. It’s conceivable to slow the disease enough that patients may never require valve replacement.” But an interview he cautioned that, “although the results are exciting, the analysis has many limitations. What we need is a dedicated, randomized trial for AS. I hope this stimulates that.”

“For VTE, it’s an interesting finding, but I don’t think it will have clinical utility because we have good treatment for VTE,” added Dr. Thanassoulis, but others saw more opportunity from what could be a new way to reduce VTE risk.

“Given that many patients have difficulty with the bleeding risk from anticoagulants, this option [a PCSK9 inhibitor] may be quite welcome for preventing VTE,” commented Gregory Piazza, MD, a cardiologist and VTE specialist at Brigham and Women’s Hospital who was not involved in any of the PCSK9 inhibitor studies.

“At this time we would not suggest that PCSK9 inhibitors replace an anticoagulant for patients with an established clot or at high risk for a recurrent clot, but if patients have an indication for a PCSK9 inhibitor, the further reduction in venous clot can be viewed as an additional benefit of this therapy,” said Dr. O’Donoghue.
 

How it might work

A possible mechanism underlying a VTE effect is unclear. Results from the JUPITER trial more than a decade ago had shown a significant association between treatment with 20 mg/day of rosuvastatin and a cut in VTE episodes, compared with placebo, in a prespecified, secondary analysis of the trial with nearly 18,000 patients selected for having a relatively high level of high-sensitivity C-reactive protein (N Engl J Med. 2009 Apr 30;360[18]:1851-61). But a meta-analysis of 29 controlled statin trials that used a variety of statin types and dosages (and included the JUPITER results) failed to confirm a statistically significant change in VTE rates from statins, though they produced a small, nominal reduction (PLoS Med. 2012 Sep 18. doi: 10.1371/journal.pmed.1001310).

Lp(a) “has long been linked to thrombosis, in particular arterial thrombosis,” so the link observed in the PCSK9 inhibitor trials “is not surprising,” said Dr. Piazza. Dr. O’Donoghue agreed that prior evidence had “suggested a prothrombotic role for Lp(a).”

Dr. Thanassoulis was more skeptical of a Lp(a) connection to VTE. “There has always been controversy regarding the prothrombotic effects of Lp(a) and whether it’s clinically relevant,” he said. “The genetic data, from Mendelian randomization studies, is not consistent” with a Lp(a) and VTE link.

The association of AS and Lp(a) may be stronger. “Our team showed that people with genetic variants that predispose to high Lp(a) have a much higher incidence of AS,” Dr. Thanassoulis noted. “We and others have also demonstrated that both Lp(a) and LDL are likely causal mediators of aortic valve calcification and stenosis.”

Dr. O’Donoghue also cited observational genetic data that linked elevated Lp(a) with AS. “Mendelian randomization studies have demonstrated that Lp(a) is a causal contributer to AS, and evolocumab reduced Lp(a) by 25%-30%, raising the possibility that Lp(a) lowering with these drugs may be the mechanism,” she said.
 

The future of Lp(a) lowering

This last point from Dr. O’Donoghue, that PCSK9 inhibitors cut Lp(a) levels by about 25%-30%, means that they are the most potent Lp(a)-lowering agents currently available, but it also leaves lots of room for other agents to do even better in cutting Lp(a).

“There are now drugs in development that block production of the Lp(a) protein and dramatically reduce its concentration, by about 80%,” Dr. O’Donoghue noted. “It will be of interest to study whether these novel therapies, now in phase 2 and phase 3 studies, have any effect on the risk for VTE and AS.”

“Several drugs in development, including antisense RNA and RNA-interfering molecules, are much more potent and lower Lp(a) by 80%-90%. Because of this potency they can completely normalize Lp(a) in most patients. For Lp(a) lowering, the future is in these new molecules. Randomized trials have started, and we will hopefully have some results in about 5 years,” said Dr. Thanassoulis.

Until then, the prospect of possibly soon documenting benefits from PCSK9 inhibitors beyond their impact on cutting LDL cholesterol raises some hope to get more bang for the considerable buck these drugs cost. But Dr. Thanassoulis was skeptical it would move the cost-benefit ratio much. “VTE and AS are relatively rare, compared with atherosclerotic cardiovascular events, and therefore the added value at the population level would be small,” he predicted. But if treatment with a drug could help patients avoid surgical or percutaneous valve interventions “that could be really interesting from a cost-benefit perspective.”

FOURIER was funded by Amgen, the company that markets evolocumab (Repatha). ODYSSEY OUTCOMES was funded by Sanofi and Regeneron, the companies that developed and market alirocumab (Praluent). Dr. Marston had no disclosures. Dr. Bergmark has been a consultant to Daiichi Sankyo, Janssen, Quark, and Servier and has received research funding from Abbott Vascular, AstraZeneca, and MedImmune. Dr. O’Donoghue has been a consultant to and has received research funding from Amgen; has been a consultant to Janssen and Novartis; and has received research funding from AstraZeneca, Eisai, GlaxoSmithKline, Janssen, Medimmune, Merck, and The Medicines Company. Dr. Thanassoulis has been an adviser to and speaker for Amgen; an adviser to Ionis and Sanofi/Regeneron; a speaker on behalf of Boehringer Ingelheim, Sanofi, and Servier; and has received research funding from Ionis and Servier. Dr. Piazza has been a consultant to Optum, Pfizer, and Thrombolex and he has received research funding from Bayer, Bristol-Myers Squibb, Daiichi Sankyo, Ekos, Janssen, and Portola.

mzoler@mdedge.com

Post hoc analyses of recent large, clinical outcomes studies of PCSK9 inhibitors have revealed two tantalizing and unexpected potential benefits from these drugs: an ability to substantially reduce the incidence or severity of venous thromboembolism and aortic stenosis.

The evidence also suggests that these effects are linked to the ability of these drugs to reduce blood levels of Lp(a) lipoprotein by roughly a quarter, currently the biggest known effect on Lp(a) levels of any approved medication.

One study ran post hoc analyses of venous thromboembolism (VTE) events in the FOURIER pivotal trial of evolocumab (Repatha), with more than 27,500 randomized patients (N Engl J Med. 2017 May 4; 376[18]:1713-22), and in the ODYSSEY OUTCOMES pivotal trial of alirocumab (Praluent), with nearly 19,000 randomized patients (N Engl J Med. 2018 Nov 29;379[22]:2097-2107). The analyses showed that, with evolocumab treatment, the incidence of VTE events fell by a statistically significant 29%, compared with patients on placebo, while in ODYSSEY OUTCOMES patients treated with alirocumab had a 33% cut in VTE events, compared with placebo-treated patients, a difference that just missed statistical significance (Circulation. 2020 Mar 29. doi: 10.1161/CIRCULATIONAHA.120.046524) in analyses that were not prespecified before these trials started, Nicholas A. Marston, MD, said in a presentation of his research during the joint scientific sessions of the American College of Cardiology and the World Heart Federation, which was presented online this year. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.

A combined analysis of 46,488 patients from both studies showed a 31% cut in VTE events with PCSK9 inhibitor treatment, a highly significant finding using VTE endpoints that were not specifically tallied nor adjudicated but collected as part of the serious adverse event reporting in the two pivotal trials, said Dr. Marston, a cardiologist at Brigham and Women’s Hospital in Boston. This is the first report of a statistically significant link between treatment with PCSK9-inhibiting agents and a reduction in VTE, he added. Researchers from the ODYSSEY OUTCOMES trial had reported a VTE analysis in 2019, and while data from that trial on its own showed a nominal 33% lower VTE rate with alirocumab treatment, it just missed statistical significance.

The VTE effect took about a year on treatment to start to manifest. During the first 12 months of FOURIER, the rate of VTE events among patients in the two treatment arms was virtually identical. But starting during months 13-18 on treatment, the event curves in the two arms began to increasingly diverge, and overall during the period from month 13 to the end of the study treatment with evolocumab was linked with a statistically significant 46% reduction in VTE events, compared with patients who received placebo. The results Dr. Marston reported were also published online (Circulation. 2020 Mar 29. doi: 10.1161/CIRCULATIONAHA.120.046397).

The suggestion that this association may be linked to the impact of PCSK9 inhibitors on Lp(a) came from an additional analysis that Dr. Marston presented, which looked at the link between evolocumab use and a change in VTE event rates, compared with placebo, depending on baseline lipoprotein levels. Evolocumab treatment was associated with a roughly similar, modest, and not statistically significant reduction in VTE events, compared with placebo regardless of whether patients had baseline levels of LDL cholesterol below the median or at or above the median. In contrast, when a similar analysis divided patients based on whether their Lp(a) level at baseline was below, or at or above, the median the results showed no discernible effect of evolocumab treatment, compared with on VTE events in patients with lower baseline Lp(a), but in those with higher levels treatment with evolocumab linked with a 48% cut in VTE events, compared with placebo, a statistically significant difference.

In FOURIER, treatment with evolocumab lowered baseline Lp(a) levels by a median of 27%, compared with placebo, among the 25,096 enrolled patients who had their baseline levels measured. As previously reported, prespecified analysis of FOURIER data also showed that the impact of evolocumab, compared with placebo, on the combined rate of coronary heart disease death, MI, or need for urgent coronary revascularization was enhanced among patients with elevated baseline Lp(a) and moderated in those who entered with lower levels. Among patients who entered FOURIER with Lp(a) levels at or below the median treatment with evolocumab cut the primary endpoint by 7%, compared with placebo, a difference that was not statistically significant. Among patients who began the study with Lp(a) levels above the median, evolocumab treatment cut the primary endpoint by 23%, compared with placebo, a statistically significant effect (Circulation. 2019 Mar 19;139[12]:1483-92).

The aortic stenosis connection

A second study reported in the online scientific sessions (Abstract 914-08) used only FOURIER data, and showed that patients treated with evolocumab had a roughly similar response pattern in their incidence of aortic stenosis (AS) events as they did for VTE events.

During the first year of the study, the incidence of AS events was virtually identical among patients treated with evolocumab and those who received placebo. But after the first 12 months and through the study’s end, patients on evolocumab showed a statistically significant 52% relative reduction in AS events, compared with control patients, said Brian A. Bergmark, MD. For the entire study duration, treatment with evolocumab linked with a 34% relative reduction in AS events, compared with placebo, a difference that did not reach statistical significance, added Dr. Bergmark, an interventional cardiologist also at Brigham and Women’s Hospital. The observed halving in total AS events that linked with evolocumab treatment after the first year of the study included a similar-magnitude reduction specifically in the incidence of aortic valve replacement procedures in the evolocumab-treated patients.

Further analysis of both total AS events and aortic valve replacements in FOURIER patients showed that they occurred at a significantly elevated rate in patients who entered the study with higher baseline Lp(a) levels in a multivariate analysis, but a similar analysis showed no significant association between the incidence of these AS-related events and baseline levels of LDL cholesterol, he said.

The AS analysis carried the same important limitations as the VTE analysis: It ran on a post hoc basis and focused on events that were relatively uncommon and not adjudicated, Dr. Bergmark cautioned. Nonetheless, other investigators saw important potential implications from both the VTE and AS observations, with the huge caveat that they need replication in prospective studies designed to specifically address the validity of these findings.
 

What it could mean

These observed associations between PCSK9 inhibitor treatment and apparent reductions in the rate of both VTE and AS events “represent a tremendous clinical breakthrough,” commented Michelle L. O’Donoghue, MD, a cardiologist at Brigham and Women’s Hospital who is a FOURIER coinvestigator and has led some of the Lp(a) analyses run from that study.

Bruce Jancin/MDedge News

“To date, we have not identified any therapies that slow progression of AS. Other classes of lipid-lowering therapies, such as statins, have been tested and not demonstrated a significant effect,” Dr. O’Donoghue said in an interview.

“For AS, the results are very intriguing. If confirmed, it could be groundbreaking. AS is the most common valve disease in the developed world, and no medical therapy exists. The potential is immense,” commented George Thanassoulis, MD, director of preventive and genomic cardiology at McGill University, Montreal. “Having a medical treatment that could slow AS progression would completely change the disease. It’s conceivable to slow the disease enough that patients may never require valve replacement.” But an interview he cautioned that, “although the results are exciting, the analysis has many limitations. What we need is a dedicated, randomized trial for AS. I hope this stimulates that.”

“For VTE, it’s an interesting finding, but I don’t think it will have clinical utility because we have good treatment for VTE,” added Dr. Thanassoulis, but others saw more opportunity from what could be a new way to reduce VTE risk.

“Given that many patients have difficulty with the bleeding risk from anticoagulants, this option [a PCSK9 inhibitor] may be quite welcome for preventing VTE,” commented Gregory Piazza, MD, a cardiologist and VTE specialist at Brigham and Women’s Hospital who was not involved in any of the PCSK9 inhibitor studies.

“At this time we would not suggest that PCSK9 inhibitors replace an anticoagulant for patients with an established clot or at high risk for a recurrent clot, but if patients have an indication for a PCSK9 inhibitor, the further reduction in venous clot can be viewed as an additional benefit of this therapy,” said Dr. O’Donoghue.
 

How it might work

A possible mechanism underlying a VTE effect is unclear. Results from the JUPITER trial more than a decade ago had shown a significant association between treatment with 20 mg/day of rosuvastatin and a cut in VTE episodes, compared with placebo, in a prespecified, secondary analysis of the trial with nearly 18,000 patients selected for having a relatively high level of high-sensitivity C-reactive protein (N Engl J Med. 2009 Apr 30;360[18]:1851-61). But a meta-analysis of 29 controlled statin trials that used a variety of statin types and dosages (and included the JUPITER results) failed to confirm a statistically significant change in VTE rates from statins, though they produced a small, nominal reduction (PLoS Med. 2012 Sep 18. doi: 10.1371/journal.pmed.1001310).

Lp(a) “has long been linked to thrombosis, in particular arterial thrombosis,” so the link observed in the PCSK9 inhibitor trials “is not surprising,” said Dr. Piazza. Dr. O’Donoghue agreed that prior evidence had “suggested a prothrombotic role for Lp(a).”

Dr. Thanassoulis was more skeptical of a Lp(a) connection to VTE. “There has always been controversy regarding the prothrombotic effects of Lp(a) and whether it’s clinically relevant,” he said. “The genetic data, from Mendelian randomization studies, is not consistent” with a Lp(a) and VTE link.

The association of AS and Lp(a) may be stronger. “Our team showed that people with genetic variants that predispose to high Lp(a) have a much higher incidence of AS,” Dr. Thanassoulis noted. “We and others have also demonstrated that both Lp(a) and LDL are likely causal mediators of aortic valve calcification and stenosis.”

Dr. O’Donoghue also cited observational genetic data that linked elevated Lp(a) with AS. “Mendelian randomization studies have demonstrated that Lp(a) is a causal contributer to AS, and evolocumab reduced Lp(a) by 25%-30%, raising the possibility that Lp(a) lowering with these drugs may be the mechanism,” she said.
 

The future of Lp(a) lowering

This last point from Dr. O’Donoghue, that PCSK9 inhibitors cut Lp(a) levels by about 25%-30%, means that they are the most potent Lp(a)-lowering agents currently available, but it also leaves lots of room for other agents to do even better in cutting Lp(a).

“There are now drugs in development that block production of the Lp(a) protein and dramatically reduce its concentration, by about 80%,” Dr. O’Donoghue noted. “It will be of interest to study whether these novel therapies, now in phase 2 and phase 3 studies, have any effect on the risk for VTE and AS.”

“Several drugs in development, including antisense RNA and RNA-interfering molecules, are much more potent and lower Lp(a) by 80%-90%. Because of this potency they can completely normalize Lp(a) in most patients. For Lp(a) lowering, the future is in these new molecules. Randomized trials have started, and we will hopefully have some results in about 5 years,” said Dr. Thanassoulis.

Until then, the prospect of possibly soon documenting benefits from PCSK9 inhibitors beyond their impact on cutting LDL cholesterol raises some hope to get more bang for the considerable buck these drugs cost. But Dr. Thanassoulis was skeptical it would move the cost-benefit ratio much. “VTE and AS are relatively rare, compared with atherosclerotic cardiovascular events, and therefore the added value at the population level would be small,” he predicted. But if treatment with a drug could help patients avoid surgical or percutaneous valve interventions “that could be really interesting from a cost-benefit perspective.”

FOURIER was funded by Amgen, the company that markets evolocumab (Repatha). ODYSSEY OUTCOMES was funded by Sanofi and Regeneron, the companies that developed and market alirocumab (Praluent). Dr. Marston had no disclosures. Dr. Bergmark has been a consultant to Daiichi Sankyo, Janssen, Quark, and Servier and has received research funding from Abbott Vascular, AstraZeneca, and MedImmune. Dr. O’Donoghue has been a consultant to and has received research funding from Amgen; has been a consultant to Janssen and Novartis; and has received research funding from AstraZeneca, Eisai, GlaxoSmithKline, Janssen, Medimmune, Merck, and The Medicines Company. Dr. Thanassoulis has been an adviser to and speaker for Amgen; an adviser to Ionis and Sanofi/Regeneron; a speaker on behalf of Boehringer Ingelheim, Sanofi, and Servier; and has received research funding from Ionis and Servier. Dr. Piazza has been a consultant to Optum, Pfizer, and Thrombolex and he has received research funding from Bayer, Bristol-Myers Squibb, Daiichi Sankyo, Ekos, Janssen, and Portola.

mzoler@mdedge.com

Post hoc analyses of recent large, clinical outcomes studies of PCSK9 inhibitors have revealed two tantalizing and unexpected potential benefits from these drugs: an ability to substantially reduce the incidence or severity of venous thromboembolism and aortic stenosis.

The evidence also suggests that these effects are linked to the ability of these drugs to reduce blood levels of Lp(a) lipoprotein by roughly a quarter, currently the biggest known effect on Lp(a) levels of any approved medication.

One study ran post hoc analyses of venous thromboembolism (VTE) events in the FOURIER pivotal trial of evolocumab (Repatha), with more than 27,500 randomized patients (N Engl J Med. 2017 May 4; 376[18]:1713-22), and in the ODYSSEY OUTCOMES pivotal trial of alirocumab (Praluent), with nearly 19,000 randomized patients (N Engl J Med. 2018 Nov 29;379[22]:2097-2107). The analyses showed that, with evolocumab treatment, the incidence of VTE events fell by a statistically significant 29%, compared with patients on placebo, while in ODYSSEY OUTCOMES patients treated with alirocumab had a 33% cut in VTE events, compared with placebo-treated patients, a difference that just missed statistical significance (Circulation. 2020 Mar 29. doi: 10.1161/CIRCULATIONAHA.120.046524) in analyses that were not prespecified before these trials started, Nicholas A. Marston, MD, said in a presentation of his research during the joint scientific sessions of the American College of Cardiology and the World Heart Federation, which was presented online this year. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.

A combined analysis of 46,488 patients from both studies showed a 31% cut in VTE events with PCSK9 inhibitor treatment, a highly significant finding using VTE endpoints that were not specifically tallied nor adjudicated but collected as part of the serious adverse event reporting in the two pivotal trials, said Dr. Marston, a cardiologist at Brigham and Women’s Hospital in Boston. This is the first report of a statistically significant link between treatment with PCSK9-inhibiting agents and a reduction in VTE, he added. Researchers from the ODYSSEY OUTCOMES trial had reported a VTE analysis in 2019, and while data from that trial on its own showed a nominal 33% lower VTE rate with alirocumab treatment, it just missed statistical significance.

The VTE effect took about a year on treatment to start to manifest. During the first 12 months of FOURIER, the rate of VTE events among patients in the two treatment arms was virtually identical. But starting during months 13-18 on treatment, the event curves in the two arms began to increasingly diverge, and overall during the period from month 13 to the end of the study treatment with evolocumab was linked with a statistically significant 46% reduction in VTE events, compared with patients who received placebo. The results Dr. Marston reported were also published online (Circulation. 2020 Mar 29. doi: 10.1161/CIRCULATIONAHA.120.046397).

The suggestion that this association may be linked to the impact of PCSK9 inhibitors on Lp(a) came from an additional analysis that Dr. Marston presented, which looked at the link between evolocumab use and a change in VTE event rates, compared with placebo, depending on baseline lipoprotein levels. Evolocumab treatment was associated with a roughly similar, modest, and not statistically significant reduction in VTE events, compared with placebo regardless of whether patients had baseline levels of LDL cholesterol below the median or at or above the median. In contrast, when a similar analysis divided patients based on whether their Lp(a) level at baseline was below, or at or above, the median the results showed no discernible effect of evolocumab treatment, compared with on VTE events in patients with lower baseline Lp(a), but in those with higher levels treatment with evolocumab linked with a 48% cut in VTE events, compared with placebo, a statistically significant difference.

In FOURIER, treatment with evolocumab lowered baseline Lp(a) levels by a median of 27%, compared with placebo, among the 25,096 enrolled patients who had their baseline levels measured. As previously reported, prespecified analysis of FOURIER data also showed that the impact of evolocumab, compared with placebo, on the combined rate of coronary heart disease death, MI, or need for urgent coronary revascularization was enhanced among patients with elevated baseline Lp(a) and moderated in those who entered with lower levels. Among patients who entered FOURIER with Lp(a) levels at or below the median treatment with evolocumab cut the primary endpoint by 7%, compared with placebo, a difference that was not statistically significant. Among patients who began the study with Lp(a) levels above the median, evolocumab treatment cut the primary endpoint by 23%, compared with placebo, a statistically significant effect (Circulation. 2019 Mar 19;139[12]:1483-92).

The aortic stenosis connection

A second study reported in the online scientific sessions (Abstract 914-08) used only FOURIER data, and showed that patients treated with evolocumab had a roughly similar response pattern in their incidence of aortic stenosis (AS) events as they did for VTE events.

During the first year of the study, the incidence of AS events was virtually identical among patients treated with evolocumab and those who received placebo. But after the first 12 months and through the study’s end, patients on evolocumab showed a statistically significant 52% relative reduction in AS events, compared with control patients, said Brian A. Bergmark, MD. For the entire study duration, treatment with evolocumab linked with a 34% relative reduction in AS events, compared with placebo, a difference that did not reach statistical significance, added Dr. Bergmark, an interventional cardiologist also at Brigham and Women’s Hospital. The observed halving in total AS events that linked with evolocumab treatment after the first year of the study included a similar-magnitude reduction specifically in the incidence of aortic valve replacement procedures in the evolocumab-treated patients.

Further analysis of both total AS events and aortic valve replacements in FOURIER patients showed that they occurred at a significantly elevated rate in patients who entered the study with higher baseline Lp(a) levels in a multivariate analysis, but a similar analysis showed no significant association between the incidence of these AS-related events and baseline levels of LDL cholesterol, he said.

The AS analysis carried the same important limitations as the VTE analysis: It ran on a post hoc basis and focused on events that were relatively uncommon and not adjudicated, Dr. Bergmark cautioned. Nonetheless, other investigators saw important potential implications from both the VTE and AS observations, with the huge caveat that they need replication in prospective studies designed to specifically address the validity of these findings.
 

What it could mean

These observed associations between PCSK9 inhibitor treatment and apparent reductions in the rate of both VTE and AS events “represent a tremendous clinical breakthrough,” commented Michelle L. O’Donoghue, MD, a cardiologist at Brigham and Women’s Hospital who is a FOURIER coinvestigator and has led some of the Lp(a) analyses run from that study.

Bruce Jancin/MDedge News

“To date, we have not identified any therapies that slow progression of AS. Other classes of lipid-lowering therapies, such as statins, have been tested and not demonstrated a significant effect,” Dr. O’Donoghue said in an interview.

“For AS, the results are very intriguing. If confirmed, it could be groundbreaking. AS is the most common valve disease in the developed world, and no medical therapy exists. The potential is immense,” commented George Thanassoulis, MD, director of preventive and genomic cardiology at McGill University, Montreal. “Having a medical treatment that could slow AS progression would completely change the disease. It’s conceivable to slow the disease enough that patients may never require valve replacement.” But an interview he cautioned that, “although the results are exciting, the analysis has many limitations. What we need is a dedicated, randomized trial for AS. I hope this stimulates that.”

“For VTE, it’s an interesting finding, but I don’t think it will have clinical utility because we have good treatment for VTE,” added Dr. Thanassoulis, but others saw more opportunity from what could be a new way to reduce VTE risk.

“Given that many patients have difficulty with the bleeding risk from anticoagulants, this option [a PCSK9 inhibitor] may be quite welcome for preventing VTE,” commented Gregory Piazza, MD, a cardiologist and VTE specialist at Brigham and Women’s Hospital who was not involved in any of the PCSK9 inhibitor studies.

“At this time we would not suggest that PCSK9 inhibitors replace an anticoagulant for patients with an established clot or at high risk for a recurrent clot, but if patients have an indication for a PCSK9 inhibitor, the further reduction in venous clot can be viewed as an additional benefit of this therapy,” said Dr. O’Donoghue.
 

How it might work

A possible mechanism underlying a VTE effect is unclear. Results from the JUPITER trial more than a decade ago had shown a significant association between treatment with 20 mg/day of rosuvastatin and a cut in VTE episodes, compared with placebo, in a prespecified, secondary analysis of the trial with nearly 18,000 patients selected for having a relatively high level of high-sensitivity C-reactive protein (N Engl J Med. 2009 Apr 30;360[18]:1851-61). But a meta-analysis of 29 controlled statin trials that used a variety of statin types and dosages (and included the JUPITER results) failed to confirm a statistically significant change in VTE rates from statins, though they produced a small, nominal reduction (PLoS Med. 2012 Sep 18. doi: 10.1371/journal.pmed.1001310).

Lp(a) “has long been linked to thrombosis, in particular arterial thrombosis,” so the link observed in the PCSK9 inhibitor trials “is not surprising,” said Dr. Piazza. Dr. O’Donoghue agreed that prior evidence had “suggested a prothrombotic role for Lp(a).”

Dr. Thanassoulis was more skeptical of a Lp(a) connection to VTE. “There has always been controversy regarding the prothrombotic effects of Lp(a) and whether it’s clinically relevant,” he said. “The genetic data, from Mendelian randomization studies, is not consistent” with a Lp(a) and VTE link.

The association of AS and Lp(a) may be stronger. “Our team showed that people with genetic variants that predispose to high Lp(a) have a much higher incidence of AS,” Dr. Thanassoulis noted. “We and others have also demonstrated that both Lp(a) and LDL are likely causal mediators of aortic valve calcification and stenosis.”

Dr. O’Donoghue also cited observational genetic data that linked elevated Lp(a) with AS. “Mendelian randomization studies have demonstrated that Lp(a) is a causal contributer to AS, and evolocumab reduced Lp(a) by 25%-30%, raising the possibility that Lp(a) lowering with these drugs may be the mechanism,” she said.
 

The future of Lp(a) lowering

This last point from Dr. O’Donoghue, that PCSK9 inhibitors cut Lp(a) levels by about 25%-30%, means that they are the most potent Lp(a)-lowering agents currently available, but it also leaves lots of room for other agents to do even better in cutting Lp(a).

“There are now drugs in development that block production of the Lp(a) protein and dramatically reduce its concentration, by about 80%,” Dr. O’Donoghue noted. “It will be of interest to study whether these novel therapies, now in phase 2 and phase 3 studies, have any effect on the risk for VTE and AS.”

“Several drugs in development, including antisense RNA and RNA-interfering molecules, are much more potent and lower Lp(a) by 80%-90%. Because of this potency they can completely normalize Lp(a) in most patients. For Lp(a) lowering, the future is in these new molecules. Randomized trials have started, and we will hopefully have some results in about 5 years,” said Dr. Thanassoulis.

Until then, the prospect of possibly soon documenting benefits from PCSK9 inhibitors beyond their impact on cutting LDL cholesterol raises some hope to get more bang for the considerable buck these drugs cost. But Dr. Thanassoulis was skeptical it would move the cost-benefit ratio much. “VTE and AS are relatively rare, compared with atherosclerotic cardiovascular events, and therefore the added value at the population level would be small,” he predicted. But if treatment with a drug could help patients avoid surgical or percutaneous valve interventions “that could be really interesting from a cost-benefit perspective.”

FOURIER was funded by Amgen, the company that markets evolocumab (Repatha). ODYSSEY OUTCOMES was funded by Sanofi and Regeneron, the companies that developed and market alirocumab (Praluent). Dr. Marston had no disclosures. Dr. Bergmark has been a consultant to Daiichi Sankyo, Janssen, Quark, and Servier and has received research funding from Abbott Vascular, AstraZeneca, and MedImmune. Dr. O’Donoghue has been a consultant to and has received research funding from Amgen; has been a consultant to Janssen and Novartis; and has received research funding from AstraZeneca, Eisai, GlaxoSmithKline, Janssen, Medimmune, Merck, and The Medicines Company. Dr. Thanassoulis has been an adviser to and speaker for Amgen; an adviser to Ionis and Sanofi/Regeneron; a speaker on behalf of Boehringer Ingelheim, Sanofi, and Servier; and has received research funding from Ionis and Servier. Dr. Piazza has been a consultant to Optum, Pfizer, and Thrombolex and he has received research funding from Bayer, Bristol-Myers Squibb, Daiichi Sankyo, Ekos, Janssen, and Portola.

mzoler@mdedge.com

ORLANDO – Combination pepinemab and avelumab is well tolerated and shows antitumor activity in patients with advanced non–small cell lung cancer (NSCLC) who progressed on prior treatment, according to interim results from a phase 1b/2 trial.

Sharon Worcester/MDedge News

Treatment with pepinemab, an anti–semaphorin 4D antibody, and avelumab, a programmed death-ligand 1 (PD-L1) inhibitor, produced disease control rates of 59% in immunotherapy-resistant patients and 81% in immunotherapy-naive patients.

Michael Rahman Shafique, MD, of Moffitt Cancer Center in Tampa, Fla., reported these results at the ASCO-SITC Clinical Immuno-Oncology Symposium.

The CLASSICAL-Lung trial initially enrolled 12 immunotherapy-naive patients with stage IIIb/IV NSCLC into a dose-escalation phase that examined pepinemab at doses of 5, 10, and 20 mg/kg along with 10 mg/kg of avelumab every 2 weeks.

Then, the trial enrolled 50 stage IIIb/IV patients – including 18 immunotherapy-naive patients and 32 who failed prior immunotherapy – into a phase 2 dose-expansion phase.

The 10 mg/kg pepinemab dose and 10 mg/kg avelumab dose were selected for the expansion phase based on the dose-escalation results, Dr. Shafique said. He explained that all three doses were safe, but “we were saturating the target at the 10-mg dose.”
 

Efficacy and safety

“In general, the safety data were encouraging,” Dr. Shafique said. “This was a very well-tolerated combination with no concerning safety signals. The most common adverse events were grade 1 and grade 2 fatigue, chills, pyrexia, and no grade 5 events attributable to the combination were reported.”

In the efficacy analysis, there were 29 evaluable patients who received pepinemab and avelumab after progressing on prior immunotherapy and were followed for at least 6 months. Two of these patients experienced a confirmed partial response (PR), and 15 had stable disease, for a disease control rate of 59%. Five patients had durable clinical benefit lasting at least 23 weeks, and three remained on active treatment at last follow-up, including one who had been on treatment for more than a year.

Of 21 evaluable immunotherapy-naive patients followed for at least 6 months, 5 experienced a confirmed PR, and 12 had stable disease, for a disease control rate of 81%. Three patients had clinical benefit lasting at least a year, and two remained on study and continued to receive treatment at last follow-up.

Pre- and on-treatment biopsies performed on the same lesion about 5 weeks apart demonstrated “a pretty drastic reduction in viable tumor,” Dr. Shafique noted.

“Even in patients with stable disease, many of them had absent tumor on these repeat, on-treatment biopsies,” he said, also noting that CD8-positive T-cell density increased in most tumors following treatment in patients who had a PR or stable disease, and the levels appeared to correspond with response.
 

Mechanism of action

Despite advances in immunotherapy, NSCLC patients often are refractory or acquire resistance to currently available agents, but semaphorin 4D “seems to shift the balance in the microenvironment to one of myeloid-induced immune suppression and generally a protumor, if you will, microenvironment,” Dr. Shafique said.

“Blockade of semaphorin 4D with pepinemab, we think, helps relieve this suppressive environment and actually seems to stimulate infiltration of T cells and improve T-cell activity in these tumors,” he added. He went on to explain that the mechanism of action is believed to generally be through suppression of myeloid cell trafficking to the tumor and myeloid cell cytokine secretion.

Further, and more importantly for cancer immunotherapy, preclinical models suggest that anti–semaphorin 4D antibodies are synergistic with various checkpoint inhibitors, including the PD-L1 inhibitor avelumab and others, Dr. Shafique said.

Indeed, these early CLASSICAL-Lung trial findings “do support the mechanism of action being reversing this myeloid-induced suppression in the microenvironment and improving T-cell infiltration and activity,” and they support a potential benefit of combining anti–semaphorin 4D antibodies and checkpoint inhibition in advanced NSCLC after progression on prior therapy, Dr. Shafique added.

Sharon Worcester/MDedge News

Invited discussant Timothy A. Yap, MBBS, of the University of Texas MD Anderson Cancer Center in Houston, said that “inhibition of [semaphorin 4D] promotes functional immune infiltration into the [tumor microenvironment] and, therefore, is a rational way of inhibiting tumor progression” in NSCLC and other cancers.

The CLASSICAL-Lung trial “didn’t escalate all the way to the [maximum tolerated dose] but did demonstrate durable on-treatment increases in CD8-positive T-cell infiltration, including in 79% of patients with low or null PD-L1 expression, as proof of mechanism,” Dr. Yap said, noting the responses in both immunotherapy-naive and immunotherapy-resistant patients.

“So I guess the key question will be, ‘Is this an active combination in NSCLC?’ ” Dr. Yap said. “In my opinion, yes it is, but is it going to be enough to take it past registration?”
 

Next steps

As next steps for the investigators, Dr. Yap suggested looking at a more specific population of PD-L1–low or –null immunotherapy-resistant NSCLC patients, considering adding a chemotherapy agent to the pepinemab/avelumab combination, or perhaps going “straight to a randomized phase 2/3 trial [comparing the combination with] pembrolizumab.”

“The investigators should also consider other tumor types beyond non–small cell lung cancer with this particular combination,” he said.

The preclinical data with respect to the anti–semaphorin 4D antibody suggest that study in combination with other agents, such as anti–CTLA-4 agents or anti-LAG3 agents, is also warranted, Dr. Yap added, noting that triplet combinations might also be worth investigating.

The CLASSICAL-Lung trial is funded by Vaccinex and Merck. Dr. Shafique reported a consulting or advisory role with GlaxoSmithKline. Dr. Yap reported relationships with numerous pharmaceutical companies, including Merck. MD Anderson’s Institute of Applied Cancer Science, where Dr. Yap serves as medical director, has a commercial interest in DNA damage response inhibitors and other inhibitors.

sworcester@mdedge.com

SOURCE: Shafique MR et al. ASCO-SITC 2020, Abstract 75.

ORLANDO – Combination pepinemab and avelumab is well tolerated and shows antitumor activity in patients with advanced non–small cell lung cancer (NSCLC) who progressed on prior treatment, according to interim results from a phase 1b/2 trial.

Sharon Worcester/MDedge News

Treatment with pepinemab, an anti–semaphorin 4D antibody, and avelumab, a programmed death-ligand 1 (PD-L1) inhibitor, produced disease control rates of 59% in immunotherapy-resistant patients and 81% in immunotherapy-naive patients.

Michael Rahman Shafique, MD, of Moffitt Cancer Center in Tampa, Fla., reported these results at the ASCO-SITC Clinical Immuno-Oncology Symposium.

The CLASSICAL-Lung trial initially enrolled 12 immunotherapy-naive patients with stage IIIb/IV NSCLC into a dose-escalation phase that examined pepinemab at doses of 5, 10, and 20 mg/kg along with 10 mg/kg of avelumab every 2 weeks.

Then, the trial enrolled 50 stage IIIb/IV patients – including 18 immunotherapy-naive patients and 32 who failed prior immunotherapy – into a phase 2 dose-expansion phase.

The 10 mg/kg pepinemab dose and 10 mg/kg avelumab dose were selected for the expansion phase based on the dose-escalation results, Dr. Shafique said. He explained that all three doses were safe, but “we were saturating the target at the 10-mg dose.”
 

Efficacy and safety

“In general, the safety data were encouraging,” Dr. Shafique said. “This was a very well-tolerated combination with no concerning safety signals. The most common adverse events were grade 1 and grade 2 fatigue, chills, pyrexia, and no grade 5 events attributable to the combination were reported.”

In the efficacy analysis, there were 29 evaluable patients who received pepinemab and avelumab after progressing on prior immunotherapy and were followed for at least 6 months. Two of these patients experienced a confirmed partial response (PR), and 15 had stable disease, for a disease control rate of 59%. Five patients had durable clinical benefit lasting at least 23 weeks, and three remained on active treatment at last follow-up, including one who had been on treatment for more than a year.

Of 21 evaluable immunotherapy-naive patients followed for at least 6 months, 5 experienced a confirmed PR, and 12 had stable disease, for a disease control rate of 81%. Three patients had clinical benefit lasting at least a year, and two remained on study and continued to receive treatment at last follow-up.

Pre- and on-treatment biopsies performed on the same lesion about 5 weeks apart demonstrated “a pretty drastic reduction in viable tumor,” Dr. Shafique noted.

“Even in patients with stable disease, many of them had absent tumor on these repeat, on-treatment biopsies,” he said, also noting that CD8-positive T-cell density increased in most tumors following treatment in patients who had a PR or stable disease, and the levels appeared to correspond with response.
 

Mechanism of action

Despite advances in immunotherapy, NSCLC patients often are refractory or acquire resistance to currently available agents, but semaphorin 4D “seems to shift the balance in the microenvironment to one of myeloid-induced immune suppression and generally a protumor, if you will, microenvironment,” Dr. Shafique said.

“Blockade of semaphorin 4D with pepinemab, we think, helps relieve this suppressive environment and actually seems to stimulate infiltration of T cells and improve T-cell activity in these tumors,” he added. He went on to explain that the mechanism of action is believed to generally be through suppression of myeloid cell trafficking to the tumor and myeloid cell cytokine secretion.

Further, and more importantly for cancer immunotherapy, preclinical models suggest that anti–semaphorin 4D antibodies are synergistic with various checkpoint inhibitors, including the PD-L1 inhibitor avelumab and others, Dr. Shafique said.

Indeed, these early CLASSICAL-Lung trial findings “do support the mechanism of action being reversing this myeloid-induced suppression in the microenvironment and improving T-cell infiltration and activity,” and they support a potential benefit of combining anti–semaphorin 4D antibodies and checkpoint inhibition in advanced NSCLC after progression on prior therapy, Dr. Shafique added.

Sharon Worcester/MDedge News

Invited discussant Timothy A. Yap, MBBS, of the University of Texas MD Anderson Cancer Center in Houston, said that “inhibition of [semaphorin 4D] promotes functional immune infiltration into the [tumor microenvironment] and, therefore, is a rational way of inhibiting tumor progression” in NSCLC and other cancers.

The CLASSICAL-Lung trial “didn’t escalate all the way to the [maximum tolerated dose] but did demonstrate durable on-treatment increases in CD8-positive T-cell infiltration, including in 79% of patients with low or null PD-L1 expression, as proof of mechanism,” Dr. Yap said, noting the responses in both immunotherapy-naive and immunotherapy-resistant patients.

“So I guess the key question will be, ‘Is this an active combination in NSCLC?’ ” Dr. Yap said. “In my opinion, yes it is, but is it going to be enough to take it past registration?”
 

Next steps

As next steps for the investigators, Dr. Yap suggested looking at a more specific population of PD-L1–low or –null immunotherapy-resistant NSCLC patients, considering adding a chemotherapy agent to the pepinemab/avelumab combination, or perhaps going “straight to a randomized phase 2/3 trial [comparing the combination with] pembrolizumab.”

“The investigators should also consider other tumor types beyond non–small cell lung cancer with this particular combination,” he said.

The preclinical data with respect to the anti–semaphorin 4D antibody suggest that study in combination with other agents, such as anti–CTLA-4 agents or anti-LAG3 agents, is also warranted, Dr. Yap added, noting that triplet combinations might also be worth investigating.

The CLASSICAL-Lung trial is funded by Vaccinex and Merck. Dr. Shafique reported a consulting or advisory role with GlaxoSmithKline. Dr. Yap reported relationships with numerous pharmaceutical companies, including Merck. MD Anderson’s Institute of Applied Cancer Science, where Dr. Yap serves as medical director, has a commercial interest in DNA damage response inhibitors and other inhibitors.

sworcester@mdedge.com

SOURCE: Shafique MR et al. ASCO-SITC 2020, Abstract 75.

ORLANDO – Combination pepinemab and avelumab is well tolerated and shows antitumor activity in patients with advanced non–small cell lung cancer (NSCLC) who progressed on prior treatment, according to interim results from a phase 1b/2 trial.

Sharon Worcester/MDedge News

Treatment with pepinemab, an anti–semaphorin 4D antibody, and avelumab, a programmed death-ligand 1 (PD-L1) inhibitor, produced disease control rates of 59% in immunotherapy-resistant patients and 81% in immunotherapy-naive patients.

Michael Rahman Shafique, MD, of Moffitt Cancer Center in Tampa, Fla., reported these results at the ASCO-SITC Clinical Immuno-Oncology Symposium.

The CLASSICAL-Lung trial initially enrolled 12 immunotherapy-naive patients with stage IIIb/IV NSCLC into a dose-escalation phase that examined pepinemab at doses of 5, 10, and 20 mg/kg along with 10 mg/kg of avelumab every 2 weeks.

Then, the trial enrolled 50 stage IIIb/IV patients – including 18 immunotherapy-naive patients and 32 who failed prior immunotherapy – into a phase 2 dose-expansion phase.

The 10 mg/kg pepinemab dose and 10 mg/kg avelumab dose were selected for the expansion phase based on the dose-escalation results, Dr. Shafique said. He explained that all three doses were safe, but “we were saturating the target at the 10-mg dose.”
 

Efficacy and safety

“In general, the safety data were encouraging,” Dr. Shafique said. “This was a very well-tolerated combination with no concerning safety signals. The most common adverse events were grade 1 and grade 2 fatigue, chills, pyrexia, and no grade 5 events attributable to the combination were reported.”

In the efficacy analysis, there were 29 evaluable patients who received pepinemab and avelumab after progressing on prior immunotherapy and were followed for at least 6 months. Two of these patients experienced a confirmed partial response (PR), and 15 had stable disease, for a disease control rate of 59%. Five patients had durable clinical benefit lasting at least 23 weeks, and three remained on active treatment at last follow-up, including one who had been on treatment for more than a year.

Of 21 evaluable immunotherapy-naive patients followed for at least 6 months, 5 experienced a confirmed PR, and 12 had stable disease, for a disease control rate of 81%. Three patients had clinical benefit lasting at least a year, and two remained on study and continued to receive treatment at last follow-up.

Pre- and on-treatment biopsies performed on the same lesion about 5 weeks apart demonstrated “a pretty drastic reduction in viable tumor,” Dr. Shafique noted.

“Even in patients with stable disease, many of them had absent tumor on these repeat, on-treatment biopsies,” he said, also noting that CD8-positive T-cell density increased in most tumors following treatment in patients who had a PR or stable disease, and the levels appeared to correspond with response.
 

Mechanism of action

Despite advances in immunotherapy, NSCLC patients often are refractory or acquire resistance to currently available agents, but semaphorin 4D “seems to shift the balance in the microenvironment to one of myeloid-induced immune suppression and generally a protumor, if you will, microenvironment,” Dr. Shafique said.

“Blockade of semaphorin 4D with pepinemab, we think, helps relieve this suppressive environment and actually seems to stimulate infiltration of T cells and improve T-cell activity in these tumors,” he added. He went on to explain that the mechanism of action is believed to generally be through suppression of myeloid cell trafficking to the tumor and myeloid cell cytokine secretion.

Further, and more importantly for cancer immunotherapy, preclinical models suggest that anti–semaphorin 4D antibodies are synergistic with various checkpoint inhibitors, including the PD-L1 inhibitor avelumab and others, Dr. Shafique said.

Indeed, these early CLASSICAL-Lung trial findings “do support the mechanism of action being reversing this myeloid-induced suppression in the microenvironment and improving T-cell infiltration and activity,” and they support a potential benefit of combining anti–semaphorin 4D antibodies and checkpoint inhibition in advanced NSCLC after progression on prior therapy, Dr. Shafique added.

Sharon Worcester/MDedge News

Invited discussant Timothy A. Yap, MBBS, of the University of Texas MD Anderson Cancer Center in Houston, said that “inhibition of [semaphorin 4D] promotes functional immune infiltration into the [tumor microenvironment] and, therefore, is a rational way of inhibiting tumor progression” in NSCLC and other cancers.

The CLASSICAL-Lung trial “didn’t escalate all the way to the [maximum tolerated dose] but did demonstrate durable on-treatment increases in CD8-positive T-cell infiltration, including in 79% of patients with low or null PD-L1 expression, as proof of mechanism,” Dr. Yap said, noting the responses in both immunotherapy-naive and immunotherapy-resistant patients.

“So I guess the key question will be, ‘Is this an active combination in NSCLC?’ ” Dr. Yap said. “In my opinion, yes it is, but is it going to be enough to take it past registration?”
 

Next steps

As next steps for the investigators, Dr. Yap suggested looking at a more specific population of PD-L1–low or –null immunotherapy-resistant NSCLC patients, considering adding a chemotherapy agent to the pepinemab/avelumab combination, or perhaps going “straight to a randomized phase 2/3 trial [comparing the combination with] pembrolizumab.”

“The investigators should also consider other tumor types beyond non–small cell lung cancer with this particular combination,” he said.

The preclinical data with respect to the anti–semaphorin 4D antibody suggest that study in combination with other agents, such as anti–CTLA-4 agents or anti-LAG3 agents, is also warranted, Dr. Yap added, noting that triplet combinations might also be worth investigating.

The CLASSICAL-Lung trial is funded by Vaccinex and Merck. Dr. Shafique reported a consulting or advisory role with GlaxoSmithKline. Dr. Yap reported relationships with numerous pharmaceutical companies, including Merck. MD Anderson’s Institute of Applied Cancer Science, where Dr. Yap serves as medical director, has a commercial interest in DNA damage response inhibitors and other inhibitors.

sworcester@mdedge.com

SOURCE: Shafique MR et al. ASCO-SITC 2020, Abstract 75.