Federal Practitioner

Opioid overdose and other preventable causes are important contributors to postpartum death rates, Medicaid claims data show, particularly in women who have a recent history of opioid use disorder (OUD), according to research published in Obstetrics and Gynecology.

Opioid overdose deaths account for up to 10% of pregnancy-associated deaths in the United States, and 75% of the deliveries of women with OUD are covered by Medicaid, according to lead author Elizabeth Suarez, PhD, MPH, with the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital and Harvard Medical School in Boston, and colleagues.
 

Nearly 5 million deliveries studied

Researchers studied claims data from Medicaid and the National Death Index database in the United States from 2006 to 2013 for 4,972,061 deliveries. They also identified a subgroup of women with a documented history of OUD in the 3 months before delivery.

They found the incidence of postpartum opioid overdose deaths was 5.4 per 100,000 deliveries (95% confidence interval, 4.5-6.4) among all in the study and 118 per 100,000 (95% CI, 84-163) among individuals with OUD.

Incidence of all-cause postpartum death was six times higher in women with OUD than in all the women studied. Common causes of death of those with OUD were other drug- and alcohol-related deaths (47/100,000); suicide (26/100,000); and other injuries, including accidents and falls (33/100,000).

Risk factors strongly linked with postpartum opioid overdose death included mental health and other substance use disorders.
 

Medication significantly lowers death risk

The authors also documented the benefit of buprenorphine or methadone for OUD.

For women with OUD who used medication to treat OUD post partum, odds of opioid overdose death were 60% lower (odds ratio, 0.4; 95% CI 0.1-0.9).

As important as use of medication, Marcela Smid, MD, MS, writes in an accompanying editorial, is noting that 80% of the women in this study who died of opioid overdoses had contact with a health care provider before death.

“Both of these results indicate that we have the means and opportunity to prevent these deaths,” writes Dr. Smid, with the division of maternal fetal medicine, University of Utah Health in Salt Lake City.
 

Dismal numbers on ob.gyns. trained to prescribe medications

She points out some barriers, however. Most clinicians, she notes, lack time and training to prescribe buprenorphine, and in 2019, fewer than 2% of ob.gyns. who accept Medicaid were able to prescribe it.

Her charge to ob.gyns.: “We need to help identify individuals who are at high risk of OUD or opioid overdose by screening.” A validated screening tool should be used at prenatal and postpartum appointments.

On a bigger scale, she urges Medicaid to be expanded for a full year post partum through the American Rescue Act’s State Plan Amendment, something only 28 states and Washington, D.C., have done so far.

Dr. Smid points out some good news, however: President Joe Biden signed the Consolidated Appropriations Act 2023, which eliminated the “X” waiver.

Now all clinicians who have a Drug Enforcement Administration registration that includes Schedule III authority can prescribe buprenorphine for OUD if applicable state law allows it.

But that calls for medical schools and residency programs to prioritize addiction medicine as a core competency, Dr. Smid says.
 

Getting naloxone to patients, families

One of the potential interventions the study authors suggest is providing naloxone prescriptions and training to pregnant and postpartum women who have a substance use history and to their partners and significant others.

However, Mishka Terplan, MD, MPH, told this publication, “It’s one thing to write a prescription; it’s another thing for the person to actually get the medication.” He is medical director of the Friends Research Institute in Baltimore, an ob.gyn. who specializes in addiction medicine.

“What can we do?” We can think about how to get naloxone into people’s hands at discharge from the hospital after they give birth, instead of prescribing. That would mean that health systems need to prioritize this, he said. “We give people discharge medications all the time.”

Still, naloxone can’t be seen as the answer, he said.

He compares it to defibrillators in public places, which are for rescues, not reversing a population problem.

“Some people think that naloxone reversals are doing something about OUD. It’s doing about as much about OUD as defibrillators do for cardiovascular disease,” he said.

The best help, he says, will be continuation of treatment.

“Addiction is a chronic condition,” he says, “but often we only provide episodic care. We see that particularly in pregnancy. Once the pregnancy is finished, there’s not categorical continuation of insurance.”

Even if you do have insurance, it’s hard to find a clinic that’s family friendly, he notes. “You might not feel comfortable taking your newborn and standing in line in the morning to get your daily methodone dose. We have to make those environments more welcoming.”
 

Problem probably understated

He also says that though the study was well done given the data available, he’s frustrated that researchers still have to depend on billing data and can’t capture factors such as child care availability, living wages, and continuation of health insurance. Additionally, not everyone is coded correctly for OUD.

“It’s all Medicaid, so it’s only people who continued with care,” he pointed out. That means these numbers may actually underrepresent the problem.

Still, he says it’s important to realize the magnitude of deaths this study does highlight in this population.

In people with OUD in the postpartum period, the deaths are more than 1 in 1,000.

“That should be alarming,” Dr. Terplan said. “That’s a very big number from a public health perspective.”

Coauthor Kathryn J. Gray received payment from Aetion Inc., Roche, and BillionToOne. Funds were paid to the University of Utah for Dr. Smid from Alydia Inc. for being the site principal investigator for a study of the JADA device, and from Gilead for Dr. Smid’s study of hepatitis C in pregnancy; she was also a consultant for Organon and Rhia Ventures. Dr. Terplan reports no relevant financial relationships.
 

Opioid overdose and other preventable causes are important contributors to postpartum death rates, Medicaid claims data show, particularly in women who have a recent history of opioid use disorder (OUD), according to research published in Obstetrics and Gynecology.

Opioid overdose deaths account for up to 10% of pregnancy-associated deaths in the United States, and 75% of the deliveries of women with OUD are covered by Medicaid, according to lead author Elizabeth Suarez, PhD, MPH, with the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital and Harvard Medical School in Boston, and colleagues.
 

Nearly 5 million deliveries studied

Researchers studied claims data from Medicaid and the National Death Index database in the United States from 2006 to 2013 for 4,972,061 deliveries. They also identified a subgroup of women with a documented history of OUD in the 3 months before delivery.

They found the incidence of postpartum opioid overdose deaths was 5.4 per 100,000 deliveries (95% confidence interval, 4.5-6.4) among all in the study and 118 per 100,000 (95% CI, 84-163) among individuals with OUD.

Incidence of all-cause postpartum death was six times higher in women with OUD than in all the women studied. Common causes of death of those with OUD were other drug- and alcohol-related deaths (47/100,000); suicide (26/100,000); and other injuries, including accidents and falls (33/100,000).

Risk factors strongly linked with postpartum opioid overdose death included mental health and other substance use disorders.
 

Medication significantly lowers death risk

The authors also documented the benefit of buprenorphine or methadone for OUD.

For women with OUD who used medication to treat OUD post partum, odds of opioid overdose death were 60% lower (odds ratio, 0.4; 95% CI 0.1-0.9).

As important as use of medication, Marcela Smid, MD, MS, writes in an accompanying editorial, is noting that 80% of the women in this study who died of opioid overdoses had contact with a health care provider before death.

“Both of these results indicate that we have the means and opportunity to prevent these deaths,” writes Dr. Smid, with the division of maternal fetal medicine, University of Utah Health in Salt Lake City.
 

Dismal numbers on ob.gyns. trained to prescribe medications

She points out some barriers, however. Most clinicians, she notes, lack time and training to prescribe buprenorphine, and in 2019, fewer than 2% of ob.gyns. who accept Medicaid were able to prescribe it.

Her charge to ob.gyns.: “We need to help identify individuals who are at high risk of OUD or opioid overdose by screening.” A validated screening tool should be used at prenatal and postpartum appointments.

On a bigger scale, she urges Medicaid to be expanded for a full year post partum through the American Rescue Act’s State Plan Amendment, something only 28 states and Washington, D.C., have done so far.

Dr. Smid points out some good news, however: President Joe Biden signed the Consolidated Appropriations Act 2023, which eliminated the “X” waiver.

Now all clinicians who have a Drug Enforcement Administration registration that includes Schedule III authority can prescribe buprenorphine for OUD if applicable state law allows it.

But that calls for medical schools and residency programs to prioritize addiction medicine as a core competency, Dr. Smid says.
 

Getting naloxone to patients, families

One of the potential interventions the study authors suggest is providing naloxone prescriptions and training to pregnant and postpartum women who have a substance use history and to their partners and significant others.

However, Mishka Terplan, MD, MPH, told this publication, “It’s one thing to write a prescription; it’s another thing for the person to actually get the medication.” He is medical director of the Friends Research Institute in Baltimore, an ob.gyn. who specializes in addiction medicine.

“What can we do?” We can think about how to get naloxone into people’s hands at discharge from the hospital after they give birth, instead of prescribing. That would mean that health systems need to prioritize this, he said. “We give people discharge medications all the time.”

Still, naloxone can’t be seen as the answer, he said.

He compares it to defibrillators in public places, which are for rescues, not reversing a population problem.

“Some people think that naloxone reversals are doing something about OUD. It’s doing about as much about OUD as defibrillators do for cardiovascular disease,” he said.

The best help, he says, will be continuation of treatment.

“Addiction is a chronic condition,” he says, “but often we only provide episodic care. We see that particularly in pregnancy. Once the pregnancy is finished, there’s not categorical continuation of insurance.”

Even if you do have insurance, it’s hard to find a clinic that’s family friendly, he notes. “You might not feel comfortable taking your newborn and standing in line in the morning to get your daily methodone dose. We have to make those environments more welcoming.”
 

Problem probably understated

He also says that though the study was well done given the data available, he’s frustrated that researchers still have to depend on billing data and can’t capture factors such as child care availability, living wages, and continuation of health insurance. Additionally, not everyone is coded correctly for OUD.

“It’s all Medicaid, so it’s only people who continued with care,” he pointed out. That means these numbers may actually underrepresent the problem.

Still, he says it’s important to realize the magnitude of deaths this study does highlight in this population.

In people with OUD in the postpartum period, the deaths are more than 1 in 1,000.

“That should be alarming,” Dr. Terplan said. “That’s a very big number from a public health perspective.”

Coauthor Kathryn J. Gray received payment from Aetion Inc., Roche, and BillionToOne. Funds were paid to the University of Utah for Dr. Smid from Alydia Inc. for being the site principal investigator for a study of the JADA device, and from Gilead for Dr. Smid’s study of hepatitis C in pregnancy; she was also a consultant for Organon and Rhia Ventures. Dr. Terplan reports no relevant financial relationships.
 

Opioid overdose and other preventable causes are important contributors to postpartum death rates, Medicaid claims data show, particularly in women who have a recent history of opioid use disorder (OUD), according to research published in Obstetrics and Gynecology.

Opioid overdose deaths account for up to 10% of pregnancy-associated deaths in the United States, and 75% of the deliveries of women with OUD are covered by Medicaid, according to lead author Elizabeth Suarez, PhD, MPH, with the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital and Harvard Medical School in Boston, and colleagues.
 

Nearly 5 million deliveries studied

Researchers studied claims data from Medicaid and the National Death Index database in the United States from 2006 to 2013 for 4,972,061 deliveries. They also identified a subgroup of women with a documented history of OUD in the 3 months before delivery.

They found the incidence of postpartum opioid overdose deaths was 5.4 per 100,000 deliveries (95% confidence interval, 4.5-6.4) among all in the study and 118 per 100,000 (95% CI, 84-163) among individuals with OUD.

Incidence of all-cause postpartum death was six times higher in women with OUD than in all the women studied. Common causes of death of those with OUD were other drug- and alcohol-related deaths (47/100,000); suicide (26/100,000); and other injuries, including accidents and falls (33/100,000).

Risk factors strongly linked with postpartum opioid overdose death included mental health and other substance use disorders.
 

Medication significantly lowers death risk

The authors also documented the benefit of buprenorphine or methadone for OUD.

For women with OUD who used medication to treat OUD post partum, odds of opioid overdose death were 60% lower (odds ratio, 0.4; 95% CI 0.1-0.9).

As important as use of medication, Marcela Smid, MD, MS, writes in an accompanying editorial, is noting that 80% of the women in this study who died of opioid overdoses had contact with a health care provider before death.

“Both of these results indicate that we have the means and opportunity to prevent these deaths,” writes Dr. Smid, with the division of maternal fetal medicine, University of Utah Health in Salt Lake City.
 

Dismal numbers on ob.gyns. trained to prescribe medications

She points out some barriers, however. Most clinicians, she notes, lack time and training to prescribe buprenorphine, and in 2019, fewer than 2% of ob.gyns. who accept Medicaid were able to prescribe it.

Her charge to ob.gyns.: “We need to help identify individuals who are at high risk of OUD or opioid overdose by screening.” A validated screening tool should be used at prenatal and postpartum appointments.

On a bigger scale, she urges Medicaid to be expanded for a full year post partum through the American Rescue Act’s State Plan Amendment, something only 28 states and Washington, D.C., have done so far.

Dr. Smid points out some good news, however: President Joe Biden signed the Consolidated Appropriations Act 2023, which eliminated the “X” waiver.

Now all clinicians who have a Drug Enforcement Administration registration that includes Schedule III authority can prescribe buprenorphine for OUD if applicable state law allows it.

But that calls for medical schools and residency programs to prioritize addiction medicine as a core competency, Dr. Smid says.
 

Getting naloxone to patients, families

One of the potential interventions the study authors suggest is providing naloxone prescriptions and training to pregnant and postpartum women who have a substance use history and to their partners and significant others.

However, Mishka Terplan, MD, MPH, told this publication, “It’s one thing to write a prescription; it’s another thing for the person to actually get the medication.” He is medical director of the Friends Research Institute in Baltimore, an ob.gyn. who specializes in addiction medicine.

“What can we do?” We can think about how to get naloxone into people’s hands at discharge from the hospital after they give birth, instead of prescribing. That would mean that health systems need to prioritize this, he said. “We give people discharge medications all the time.”

Still, naloxone can’t be seen as the answer, he said.

He compares it to defibrillators in public places, which are for rescues, not reversing a population problem.

“Some people think that naloxone reversals are doing something about OUD. It’s doing about as much about OUD as defibrillators do for cardiovascular disease,” he said.

The best help, he says, will be continuation of treatment.

“Addiction is a chronic condition,” he says, “but often we only provide episodic care. We see that particularly in pregnancy. Once the pregnancy is finished, there’s not categorical continuation of insurance.”

Even if you do have insurance, it’s hard to find a clinic that’s family friendly, he notes. “You might not feel comfortable taking your newborn and standing in line in the morning to get your daily methodone dose. We have to make those environments more welcoming.”
 

Problem probably understated

He also says that though the study was well done given the data available, he’s frustrated that researchers still have to depend on billing data and can’t capture factors such as child care availability, living wages, and continuation of health insurance. Additionally, not everyone is coded correctly for OUD.

“It’s all Medicaid, so it’s only people who continued with care,” he pointed out. That means these numbers may actually underrepresent the problem.

Still, he says it’s important to realize the magnitude of deaths this study does highlight in this population.

In people with OUD in the postpartum period, the deaths are more than 1 in 1,000.

“That should be alarming,” Dr. Terplan said. “That’s a very big number from a public health perspective.”

Coauthor Kathryn J. Gray received payment from Aetion Inc., Roche, and BillionToOne. Funds were paid to the University of Utah for Dr. Smid from Alydia Inc. for being the site principal investigator for a study of the JADA device, and from Gilead for Dr. Smid’s study of hepatitis C in pregnancy; she was also a consultant for Organon and Rhia Ventures. Dr. Terplan reports no relevant financial relationships.
 

When the Food and Drug Administration approved avacopan (Tavneos) as an adjunctive treatment for severe, active antineutrophil cytoplasmic autoantibody (ANCA)–associated vasculitis (AAV) in October 2021, the oral complement C5a receptor inhibitor was hailed by its developer, ChemoCentryx, as a “new hope” for patients with the disease.

But avacopan’s novelty as a new drug for the rare diseases granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), coupled with its approval as an adjunctive to standard therapy, including glucocorticoids, rather than strictly as a glucocorticoid-sparing agent as it was tested, has so far led to little reported real-world experience with the drug.

M. Alexander Otto

In the phase 3 ADVOCATE trial, the pivotal trial that served as the basis for avacopan’s approval, 331 patients with active newly diagnosed or relapsing GPA or MPA received either avacopan or an oral prednisone taper over 20 weeks on a background of cyclophosphamide followed by azathioprine or rituximab. The results of the trial showed avacopan was noninferior to the group that received prednisone taper for remission at 26 weeks and superior to prednisone taper for sustained remission at 52 weeks, but the FDA was concerned that its complex design made it difficult to define the clinically meaningful benefit of avacopan and its role in the management of AAV.

The FDA noted that, in the avacopan arm of the trial, 86% of patients received glucocorticoids outside of the study protocol. Despite this, avacopan reduced the cumulative glucocorticoid dose over the trial’s 52 weeks by nearly two-thirds, compared with the prednisone group (1,349 mg vs. 3,655 mg).

The data also indicate a higher sustained remission rate at 52 weeks in patients who received induction with rituximab, compared with cyclophosphamide. But trial did not include a maintenance therapy dose of rituximab and is thereby not a good comparison against the standard of care, the FDA said. (ADVOCATE began enrolling patients prior to the FDA's 2018 approval of an expanded indication for patients with GPA or MPA who have achieved disease control after induction treatment.)

At the FDA’s Arthritis Advisory Committee meeting in May 2021, committee members were split on whether to recommend avacopan for approval. The committee voted 9-9 on whether the ADVOCATE trial showed efficacy supporting approval of avacopan, 10-8 in favor of whether the drug’s safety profile supported approval, and 10-8 in favor of the overall benefit-risk profile of avacopan for approval. But rather than give an indication to avacopan to reduce the use of glucocorticoids in adults with GPA or MPA, the agency approved avacopan as an adjunctive treatment for severe, active disease, noting in particular that avacopan “does not eliminate glucocorticoid use.”

The European Union’s marketing authorization for avacopan states its indication for use in combination with a rituximab or cyclophosphamide regimen for the treatment of adult patients with severe, active GPA or MPA and does not mention a role for reducing glucocorticoids. Avacopan will appear in forthcoming guidelines on management of AAV released by the European Alliance of Associations for Rheumatology.

In North America, the Canadian Vasculitis Research Network recently released an addendum to their guidelines on AAV specifically for avacopan, which includes recommendations to consider adding oral avacopan (30 mg twice daily) for induction of remission in patients with new or relapsing GPA or MPA who are also receiving cyclophosphamide or rituximab. The guidelines also recommend clinicians consider a glucocorticoid tapering schedule that aims for discontinuation at 4 weeks, and continuing avacopan for at least 1 year after induction therapy. The American College of Rheumatology guideline for AAV management, updated in 2021, acknowledges avacopan but did not consider its inclusion prior to FDA approval.

There have been few real-world studies of how patients with AAV are responding to avacopan, but recent studies from researchers in the Netherlands and in France have evaluated prednisone tapering and clinical outcomes.

Anisha B. Dua, MD, an associate professor of rheumatology at Northwestern University, Chicago, said those real-world studies “seemed to re-enforce the findings from the ADVOCATE study demonstrating the efficacy of avacopan in severe disease with steroid-sparing effects.”

However, Carol Langford, MD, MHS, director of the Center for Vasculitis Care and Research at the Cleveland Clinic, emphasized caution is needed when drawing conclusions about avacopan use outside formal studies.

“We are all interested in what other settings this might be used. I think those are things that really require formal investigation to really try and understand better as far as through a study process,” she said.
 

Prescribing experience with avacopan

A spokesperson from Amgen, which recently acquired ChemoCentryx, said in an interview that over 800 physicians in the United States have prescribed avacopan to patients with new or relapsing ANCA-associated vasculitis as induction or maintenance treatment, and physicians have reported outcomes consistent with the ADVOCATE trial.

Many rheumatologists are likely familiar with avacopan but are not used to prescribing it, said Lindsay S. Lally, MD, a rheumatologist with Hospital for Special Surgery in New York.

“Rituximab was approved for GPA and MPA a decade ago at this point. It was a drug that we as rheumatologists were used to using. We used it for other indications. Avacopan is a totally new drug, a new mechanism of action, so there’s not a lot of extractable data that we have in terms of comfort with the drug, and so I think that’s one of the biggest hurdles,” she said.

Mehrnaz Hojjati, MD, a rheumatologist with Loma Linda (Calif.) University Health, said that, when the FDA approved avacopan, it was an “exciting time” in her practice. “I have used avacopan now in a handful of my patients with severe ANCA-associated vasculitis, and the results are similar to what [was] reported in the ADVOCATE trial.”

Amgen offers help for clinicians in obtaining avacopan for patients, financial assistance for patients, and support in navigating insurance, which several rheumatologists noted was important for patients. Dr. Langford said the process of working with the manufacturer to get avacopan while insurance information is being processed has been “fairly smooth.”

“Certainly, the ability to get a very rapid 30-day supply with the goal of trying to initiate this as early as possible in the disease process has been helpful,” she said.

In Dr. Dua’s experience, while there were “some glitches or difficulty for providers early on” in how to access and prescribe avacopan, since then “it has been much easier to obtain the medication with the first month being provided to patients free while the authorization process is managed.”

Prescribing avacopan from inpatient pharmacies has been more challenging, she said. “The inpatient side is trickier because each hospital system has their own pharmacy system and regulations that have to be navigated. For outpatients, all the provider needs to do is fill out the start form available on their website, have the patients sign it, and then have it sent in.”
 

Concerns about affordability, insurance approval

Another consideration is cost, with avacopan having an estimated price of $150,000-$200,000 per patient per year.

Dr. Hojjati noted that, while it is easy to prescribe, avacopan is hard to get approved through insurance. “We face the same challenge every time a new medication comes to the market on how to convince the payers to pay for it given higher prices,” she said.

Rheumatologist Michael Putman, MD, MSCI, assistant professor of medicine at the Medical College of Wisconsin, Milwaukee, also acknowledged some difficulties in prescribing the medication. “The insurance companies have no interest in spending $150,000 on a drug that they know nothing about, and patients are a little hesitant to take it because it’s just so new,” he said.

While Dr. Lally said avacopan has not been difficult to get for patients with commercial insurance, reimbursement through Medicare has been problematic. “In many of the Medicare patients it has not really been a feasible option for them to be on the drug for the year of therapy.”
 

Patient response

Dr. Dua said almost all her patients with new or relapsing AAV who require induction are being prescribed avacopan, and that the medication is well tolerated. “The remission and ability to wean prednisone has really paralleled the findings from the clinical trial.”

In her practice, Dr. Hojjati starts patients on avacopan immediately after discharge from the hospital after a major vasculitis flare requiring high-dose glucocorticoids. “Avacopan does not eliminate/replace GC [glucocorticoid] use but has a notable GC-sparing effect and assists in rapid tapering of the GC while treating our severe ANCA-associated vasculitis patients,” she said.

Dr. Lally said her patients are tolerating avacopan well and hasn’t seen any of the safety signals seen in the trial, including liver function abnormalities. She has treated about 20-25 patients with avacopan.

Dr. Putman noted that he has treated about five patients with avacopan but hasn’t seen dramatic efficacy or side effects in his practice, compared with standard therapy.

Unanswered questions about avacopan

A key unanswered question with avacopan is the timeline for tapering glucocorticoids once patients start treatment. “I would like to see much more data on how prednisone is being tapered in clinical practice as well as outcomes in patients who are treated with the standard of care second dose of rituximab at 6 months,” Dr. Dua said.

Dr. Lally noted she has tried to expedite the steroid taper in her patients. “That’s really where I feel this drug is going to have most relevance, is getting it started early in active disease and getting patients off of the reliance on high doses of oral steroids. I have been able to see that in practice, and I do think ultimately that’s going to lead to better outcomes and quality of life for these patients.”

Of the rheumatologists Dr. Lally has spoken to about avacopan, there is “some confusion about what type of patients are appropriate, [and] how sick or not sick the patient needs to be.”

Dr. Putman noted he is unsure which of his patients should be receiving avacopan. “I don’t totally have a sense for where avacopan stands and how often we should be using it” outside of patients with severe disease. He added that the drug is still trying to find a niche because most patients with AAV who take rituximab and steroids get better without additional treatments.

“I think we do a pretty good job treating these diseases even in the preavacopan era. But it’s really a matter of how to really optimize these outcomes, reduce damage, reduce steroid-related and treatment-related toxicity for our patients,” Dr. Lally said.

Dr. Dua reported being a consultant and serving on advisory boards for ChemoCentryx; she was also a site principal investigator for the ADVOCATE trial. Dr. Hojjati reported being on the speaker’s bureau for Amgen. Dr. Langford reported being an investigator in the ADVOCATE trial, and her institution received funding to conduct the trial. Dr. Lally reported being a consultant for Amgen on avacopan. Dr. Putman reported no relevant financial disclosures.

*This story was updated 3/15/2023.

When the Food and Drug Administration approved avacopan (Tavneos) as an adjunctive treatment for severe, active antineutrophil cytoplasmic autoantibody (ANCA)–associated vasculitis (AAV) in October 2021, the oral complement C5a receptor inhibitor was hailed by its developer, ChemoCentryx, as a “new hope” for patients with the disease.

But avacopan’s novelty as a new drug for the rare diseases granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), coupled with its approval as an adjunctive to standard therapy, including glucocorticoids, rather than strictly as a glucocorticoid-sparing agent as it was tested, has so far led to little reported real-world experience with the drug.

M. Alexander Otto

In the phase 3 ADVOCATE trial, the pivotal trial that served as the basis for avacopan’s approval, 331 patients with active newly diagnosed or relapsing GPA or MPA received either avacopan or an oral prednisone taper over 20 weeks on a background of cyclophosphamide followed by azathioprine or rituximab. The results of the trial showed avacopan was noninferior to the group that received prednisone taper for remission at 26 weeks and superior to prednisone taper for sustained remission at 52 weeks, but the FDA was concerned that its complex design made it difficult to define the clinically meaningful benefit of avacopan and its role in the management of AAV.

The FDA noted that, in the avacopan arm of the trial, 86% of patients received glucocorticoids outside of the study protocol. Despite this, avacopan reduced the cumulative glucocorticoid dose over the trial’s 52 weeks by nearly two-thirds, compared with the prednisone group (1,349 mg vs. 3,655 mg).

The data also indicate a higher sustained remission rate at 52 weeks in patients who received induction with rituximab, compared with cyclophosphamide. But trial did not include a maintenance therapy dose of rituximab and is thereby not a good comparison against the standard of care, the FDA said. (ADVOCATE began enrolling patients prior to the FDA's 2018 approval of an expanded indication for patients with GPA or MPA who have achieved disease control after induction treatment.)

At the FDA’s Arthritis Advisory Committee meeting in May 2021, committee members were split on whether to recommend avacopan for approval. The committee voted 9-9 on whether the ADVOCATE trial showed efficacy supporting approval of avacopan, 10-8 in favor of whether the drug’s safety profile supported approval, and 10-8 in favor of the overall benefit-risk profile of avacopan for approval. But rather than give an indication to avacopan to reduce the use of glucocorticoids in adults with GPA or MPA, the agency approved avacopan as an adjunctive treatment for severe, active disease, noting in particular that avacopan “does not eliminate glucocorticoid use.”

The European Union’s marketing authorization for avacopan states its indication for use in combination with a rituximab or cyclophosphamide regimen for the treatment of adult patients with severe, active GPA or MPA and does not mention a role for reducing glucocorticoids. Avacopan will appear in forthcoming guidelines on management of AAV released by the European Alliance of Associations for Rheumatology.

In North America, the Canadian Vasculitis Research Network recently released an addendum to their guidelines on AAV specifically for avacopan, which includes recommendations to consider adding oral avacopan (30 mg twice daily) for induction of remission in patients with new or relapsing GPA or MPA who are also receiving cyclophosphamide or rituximab. The guidelines also recommend clinicians consider a glucocorticoid tapering schedule that aims for discontinuation at 4 weeks, and continuing avacopan for at least 1 year after induction therapy. The American College of Rheumatology guideline for AAV management, updated in 2021, acknowledges avacopan but did not consider its inclusion prior to FDA approval.

There have been few real-world studies of how patients with AAV are responding to avacopan, but recent studies from researchers in the Netherlands and in France have evaluated prednisone tapering and clinical outcomes.

Anisha B. Dua, MD, an associate professor of rheumatology at Northwestern University, Chicago, said those real-world studies “seemed to re-enforce the findings from the ADVOCATE study demonstrating the efficacy of avacopan in severe disease with steroid-sparing effects.”

However, Carol Langford, MD, MHS, director of the Center for Vasculitis Care and Research at the Cleveland Clinic, emphasized caution is needed when drawing conclusions about avacopan use outside formal studies.

“We are all interested in what other settings this might be used. I think those are things that really require formal investigation to really try and understand better as far as through a study process,” she said.
 

Prescribing experience with avacopan

A spokesperson from Amgen, which recently acquired ChemoCentryx, said in an interview that over 800 physicians in the United States have prescribed avacopan to patients with new or relapsing ANCA-associated vasculitis as induction or maintenance treatment, and physicians have reported outcomes consistent with the ADVOCATE trial.

Many rheumatologists are likely familiar with avacopan but are not used to prescribing it, said Lindsay S. Lally, MD, a rheumatologist with Hospital for Special Surgery in New York.

“Rituximab was approved for GPA and MPA a decade ago at this point. It was a drug that we as rheumatologists were used to using. We used it for other indications. Avacopan is a totally new drug, a new mechanism of action, so there’s not a lot of extractable data that we have in terms of comfort with the drug, and so I think that’s one of the biggest hurdles,” she said.

Mehrnaz Hojjati, MD, a rheumatologist with Loma Linda (Calif.) University Health, said that, when the FDA approved avacopan, it was an “exciting time” in her practice. “I have used avacopan now in a handful of my patients with severe ANCA-associated vasculitis, and the results are similar to what [was] reported in the ADVOCATE trial.”

Amgen offers help for clinicians in obtaining avacopan for patients, financial assistance for patients, and support in navigating insurance, which several rheumatologists noted was important for patients. Dr. Langford said the process of working with the manufacturer to get avacopan while insurance information is being processed has been “fairly smooth.”

“Certainly, the ability to get a very rapid 30-day supply with the goal of trying to initiate this as early as possible in the disease process has been helpful,” she said.

In Dr. Dua’s experience, while there were “some glitches or difficulty for providers early on” in how to access and prescribe avacopan, since then “it has been much easier to obtain the medication with the first month being provided to patients free while the authorization process is managed.”

Prescribing avacopan from inpatient pharmacies has been more challenging, she said. “The inpatient side is trickier because each hospital system has their own pharmacy system and regulations that have to be navigated. For outpatients, all the provider needs to do is fill out the start form available on their website, have the patients sign it, and then have it sent in.”
 

Concerns about affordability, insurance approval

Another consideration is cost, with avacopan having an estimated price of $150,000-$200,000 per patient per year.

Dr. Hojjati noted that, while it is easy to prescribe, avacopan is hard to get approved through insurance. “We face the same challenge every time a new medication comes to the market on how to convince the payers to pay for it given higher prices,” she said.

Rheumatologist Michael Putman, MD, MSCI, assistant professor of medicine at the Medical College of Wisconsin, Milwaukee, also acknowledged some difficulties in prescribing the medication. “The insurance companies have no interest in spending $150,000 on a drug that they know nothing about, and patients are a little hesitant to take it because it’s just so new,” he said.

While Dr. Lally said avacopan has not been difficult to get for patients with commercial insurance, reimbursement through Medicare has been problematic. “In many of the Medicare patients it has not really been a feasible option for them to be on the drug for the year of therapy.”
 

Patient response

Dr. Dua said almost all her patients with new or relapsing AAV who require induction are being prescribed avacopan, and that the medication is well tolerated. “The remission and ability to wean prednisone has really paralleled the findings from the clinical trial.”

In her practice, Dr. Hojjati starts patients on avacopan immediately after discharge from the hospital after a major vasculitis flare requiring high-dose glucocorticoids. “Avacopan does not eliminate/replace GC [glucocorticoid] use but has a notable GC-sparing effect and assists in rapid tapering of the GC while treating our severe ANCA-associated vasculitis patients,” she said.

Dr. Lally said her patients are tolerating avacopan well and hasn’t seen any of the safety signals seen in the trial, including liver function abnormalities. She has treated about 20-25 patients with avacopan.

Dr. Putman noted that he has treated about five patients with avacopan but hasn’t seen dramatic efficacy or side effects in his practice, compared with standard therapy.

Unanswered questions about avacopan

A key unanswered question with avacopan is the timeline for tapering glucocorticoids once patients start treatment. “I would like to see much more data on how prednisone is being tapered in clinical practice as well as outcomes in patients who are treated with the standard of care second dose of rituximab at 6 months,” Dr. Dua said.

Dr. Lally noted she has tried to expedite the steroid taper in her patients. “That’s really where I feel this drug is going to have most relevance, is getting it started early in active disease and getting patients off of the reliance on high doses of oral steroids. I have been able to see that in practice, and I do think ultimately that’s going to lead to better outcomes and quality of life for these patients.”

Of the rheumatologists Dr. Lally has spoken to about avacopan, there is “some confusion about what type of patients are appropriate, [and] how sick or not sick the patient needs to be.”

Dr. Putman noted he is unsure which of his patients should be receiving avacopan. “I don’t totally have a sense for where avacopan stands and how often we should be using it” outside of patients with severe disease. He added that the drug is still trying to find a niche because most patients with AAV who take rituximab and steroids get better without additional treatments.

“I think we do a pretty good job treating these diseases even in the preavacopan era. But it’s really a matter of how to really optimize these outcomes, reduce damage, reduce steroid-related and treatment-related toxicity for our patients,” Dr. Lally said.

Dr. Dua reported being a consultant and serving on advisory boards for ChemoCentryx; she was also a site principal investigator for the ADVOCATE trial. Dr. Hojjati reported being on the speaker’s bureau for Amgen. Dr. Langford reported being an investigator in the ADVOCATE trial, and her institution received funding to conduct the trial. Dr. Lally reported being a consultant for Amgen on avacopan. Dr. Putman reported no relevant financial disclosures.

*This story was updated 3/15/2023.

When the Food and Drug Administration approved avacopan (Tavneos) as an adjunctive treatment for severe, active antineutrophil cytoplasmic autoantibody (ANCA)–associated vasculitis (AAV) in October 2021, the oral complement C5a receptor inhibitor was hailed by its developer, ChemoCentryx, as a “new hope” for patients with the disease.

But avacopan’s novelty as a new drug for the rare diseases granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), coupled with its approval as an adjunctive to standard therapy, including glucocorticoids, rather than strictly as a glucocorticoid-sparing agent as it was tested, has so far led to little reported real-world experience with the drug.

M. Alexander Otto

In the phase 3 ADVOCATE trial, the pivotal trial that served as the basis for avacopan’s approval, 331 patients with active newly diagnosed or relapsing GPA or MPA received either avacopan or an oral prednisone taper over 20 weeks on a background of cyclophosphamide followed by azathioprine or rituximab. The results of the trial showed avacopan was noninferior to the group that received prednisone taper for remission at 26 weeks and superior to prednisone taper for sustained remission at 52 weeks, but the FDA was concerned that its complex design made it difficult to define the clinically meaningful benefit of avacopan and its role in the management of AAV.

The FDA noted that, in the avacopan arm of the trial, 86% of patients received glucocorticoids outside of the study protocol. Despite this, avacopan reduced the cumulative glucocorticoid dose over the trial’s 52 weeks by nearly two-thirds, compared with the prednisone group (1,349 mg vs. 3,655 mg).

The data also indicate a higher sustained remission rate at 52 weeks in patients who received induction with rituximab, compared with cyclophosphamide. But trial did not include a maintenance therapy dose of rituximab and is thereby not a good comparison against the standard of care, the FDA said. (ADVOCATE began enrolling patients prior to the FDA's 2018 approval of an expanded indication for patients with GPA or MPA who have achieved disease control after induction treatment.)

At the FDA’s Arthritis Advisory Committee meeting in May 2021, committee members were split on whether to recommend avacopan for approval. The committee voted 9-9 on whether the ADVOCATE trial showed efficacy supporting approval of avacopan, 10-8 in favor of whether the drug’s safety profile supported approval, and 10-8 in favor of the overall benefit-risk profile of avacopan for approval. But rather than give an indication to avacopan to reduce the use of glucocorticoids in adults with GPA or MPA, the agency approved avacopan as an adjunctive treatment for severe, active disease, noting in particular that avacopan “does not eliminate glucocorticoid use.”

The European Union’s marketing authorization for avacopan states its indication for use in combination with a rituximab or cyclophosphamide regimen for the treatment of adult patients with severe, active GPA or MPA and does not mention a role for reducing glucocorticoids. Avacopan will appear in forthcoming guidelines on management of AAV released by the European Alliance of Associations for Rheumatology.

In North America, the Canadian Vasculitis Research Network recently released an addendum to their guidelines on AAV specifically for avacopan, which includes recommendations to consider adding oral avacopan (30 mg twice daily) for induction of remission in patients with new or relapsing GPA or MPA who are also receiving cyclophosphamide or rituximab. The guidelines also recommend clinicians consider a glucocorticoid tapering schedule that aims for discontinuation at 4 weeks, and continuing avacopan for at least 1 year after induction therapy. The American College of Rheumatology guideline for AAV management, updated in 2021, acknowledges avacopan but did not consider its inclusion prior to FDA approval.

There have been few real-world studies of how patients with AAV are responding to avacopan, but recent studies from researchers in the Netherlands and in France have evaluated prednisone tapering and clinical outcomes.

Anisha B. Dua, MD, an associate professor of rheumatology at Northwestern University, Chicago, said those real-world studies “seemed to re-enforce the findings from the ADVOCATE study demonstrating the efficacy of avacopan in severe disease with steroid-sparing effects.”

However, Carol Langford, MD, MHS, director of the Center for Vasculitis Care and Research at the Cleveland Clinic, emphasized caution is needed when drawing conclusions about avacopan use outside formal studies.

“We are all interested in what other settings this might be used. I think those are things that really require formal investigation to really try and understand better as far as through a study process,” she said.
 

Prescribing experience with avacopan

A spokesperson from Amgen, which recently acquired ChemoCentryx, said in an interview that over 800 physicians in the United States have prescribed avacopan to patients with new or relapsing ANCA-associated vasculitis as induction or maintenance treatment, and physicians have reported outcomes consistent with the ADVOCATE trial.

Many rheumatologists are likely familiar with avacopan but are not used to prescribing it, said Lindsay S. Lally, MD, a rheumatologist with Hospital for Special Surgery in New York.

“Rituximab was approved for GPA and MPA a decade ago at this point. It was a drug that we as rheumatologists were used to using. We used it for other indications. Avacopan is a totally new drug, a new mechanism of action, so there’s not a lot of extractable data that we have in terms of comfort with the drug, and so I think that’s one of the biggest hurdles,” she said.

Mehrnaz Hojjati, MD, a rheumatologist with Loma Linda (Calif.) University Health, said that, when the FDA approved avacopan, it was an “exciting time” in her practice. “I have used avacopan now in a handful of my patients with severe ANCA-associated vasculitis, and the results are similar to what [was] reported in the ADVOCATE trial.”

Amgen offers help for clinicians in obtaining avacopan for patients, financial assistance for patients, and support in navigating insurance, which several rheumatologists noted was important for patients. Dr. Langford said the process of working with the manufacturer to get avacopan while insurance information is being processed has been “fairly smooth.”

“Certainly, the ability to get a very rapid 30-day supply with the goal of trying to initiate this as early as possible in the disease process has been helpful,” she said.

In Dr. Dua’s experience, while there were “some glitches or difficulty for providers early on” in how to access and prescribe avacopan, since then “it has been much easier to obtain the medication with the first month being provided to patients free while the authorization process is managed.”

Prescribing avacopan from inpatient pharmacies has been more challenging, she said. “The inpatient side is trickier because each hospital system has their own pharmacy system and regulations that have to be navigated. For outpatients, all the provider needs to do is fill out the start form available on their website, have the patients sign it, and then have it sent in.”
 

Concerns about affordability, insurance approval

Another consideration is cost, with avacopan having an estimated price of $150,000-$200,000 per patient per year.

Dr. Hojjati noted that, while it is easy to prescribe, avacopan is hard to get approved through insurance. “We face the same challenge every time a new medication comes to the market on how to convince the payers to pay for it given higher prices,” she said.

Rheumatologist Michael Putman, MD, MSCI, assistant professor of medicine at the Medical College of Wisconsin, Milwaukee, also acknowledged some difficulties in prescribing the medication. “The insurance companies have no interest in spending $150,000 on a drug that they know nothing about, and patients are a little hesitant to take it because it’s just so new,” he said.

While Dr. Lally said avacopan has not been difficult to get for patients with commercial insurance, reimbursement through Medicare has been problematic. “In many of the Medicare patients it has not really been a feasible option for them to be on the drug for the year of therapy.”
 

Patient response

Dr. Dua said almost all her patients with new or relapsing AAV who require induction are being prescribed avacopan, and that the medication is well tolerated. “The remission and ability to wean prednisone has really paralleled the findings from the clinical trial.”

In her practice, Dr. Hojjati starts patients on avacopan immediately after discharge from the hospital after a major vasculitis flare requiring high-dose glucocorticoids. “Avacopan does not eliminate/replace GC [glucocorticoid] use but has a notable GC-sparing effect and assists in rapid tapering of the GC while treating our severe ANCA-associated vasculitis patients,” she said.

Dr. Lally said her patients are tolerating avacopan well and hasn’t seen any of the safety signals seen in the trial, including liver function abnormalities. She has treated about 20-25 patients with avacopan.

Dr. Putman noted that he has treated about five patients with avacopan but hasn’t seen dramatic efficacy or side effects in his practice, compared with standard therapy.

Unanswered questions about avacopan

A key unanswered question with avacopan is the timeline for tapering glucocorticoids once patients start treatment. “I would like to see much more data on how prednisone is being tapered in clinical practice as well as outcomes in patients who are treated with the standard of care second dose of rituximab at 6 months,” Dr. Dua said.

Dr. Lally noted she has tried to expedite the steroid taper in her patients. “That’s really where I feel this drug is going to have most relevance, is getting it started early in active disease and getting patients off of the reliance on high doses of oral steroids. I have been able to see that in practice, and I do think ultimately that’s going to lead to better outcomes and quality of life for these patients.”

Of the rheumatologists Dr. Lally has spoken to about avacopan, there is “some confusion about what type of patients are appropriate, [and] how sick or not sick the patient needs to be.”

Dr. Putman noted he is unsure which of his patients should be receiving avacopan. “I don’t totally have a sense for where avacopan stands and how often we should be using it” outside of patients with severe disease. He added that the drug is still trying to find a niche because most patients with AAV who take rituximab and steroids get better without additional treatments.

“I think we do a pretty good job treating these diseases even in the preavacopan era. But it’s really a matter of how to really optimize these outcomes, reduce damage, reduce steroid-related and treatment-related toxicity for our patients,” Dr. Lally said.

Dr. Dua reported being a consultant and serving on advisory boards for ChemoCentryx; she was also a site principal investigator for the ADVOCATE trial. Dr. Hojjati reported being on the speaker’s bureau for Amgen. Dr. Langford reported being an investigator in the ADVOCATE trial, and her institution received funding to conduct the trial. Dr. Lally reported being a consultant for Amgen on avacopan. Dr. Putman reported no relevant financial disclosures.

*This story was updated 3/15/2023.

One morning I stepped into the elevator in the lobby of the US Department of Veterans Affairs (VA) medical center where I work, holding a cup of coffee, joining another staffer, a middle-aged man, wearing a veteran’s pin on his employee badge. An older veteran slowly approached the elevator doors, shuffling with each step, and since he was at the front of the elevator, he cheerfully bellowed “Which floor?” as he offered to push the button for us.

“What’s on 12?” he asked in a jovial voice. I smiled. “Aging research,” referring to the Geriatrics Research Education and Clinical Center where I work.¹

“I definitely need that—I forgot where I’m going!” he joked, his fingers hovering over the elevator buttons.

As we reached his floor, the doors opened, he waved with a smile and unsteadily made his way out of the elevator and down the hall to his appointment. As the elevator doors closed behind him, the other staffer turned to me and said with a shrug, “That’ll be me one day,” as he got off at the next floor.

When I got off the elevator and walked toward my office, I reflected on the care that I as a geriatrician and we at the VA hope to provide to aging veterans, now and in the future: Age-Friendly care. Age-Friendly means the compassionate care that we want for those who have served our country, for our loved ones, and for ourselves as we age. Age-Friendly means person-centered, evidence-based care that as we grow older will help us to address challenges that may come with older age, such as falls, cognitive impairment, and polypharmacy. Too often the health care system remains focused on the chief concern or on a clinician’s specialty and may not focus on those important areas where we can potentially intervene to support aging veterans.

The VA has set a goal to become the largest Age-Friendly Health System (AFHS) in the country.² Led by the Institute for Healthcare Improvement and funded by the John A. Hartford Foundation, the Age-Friendly Health Systems Initiative aims to help clinicians and care settings “follow an essential set of evidence-based practices; cause no harm; and align with what matters to the older adult and their family caregivers.”³ An AFHS cares for older adults with attention to the 4Ms—What Matters, Mobility, Mentation, and Medications.⁴ Specifically, in an AFHS, older adults are asked what matters to them so we can align their health care with their goals; clinicians evaluate veterans for safe mobility and fall risk reduction, cognitive impairment and mood disorders, and identify and avoid high-risk medications.⁵ In an AFHS, the 4Ms are practiced as a set, reliably, across settings, so that there should be no wrong door or wrong floor for an older veteran to receive Age-Friendly care within the VA health care system.⁶

Too often our health care system and health professions education have left clinicians unprepared to care for older adults using an Age-Friendly framework; rather, we have been trained in problem-based or disease-based care that can miss the forest for the trees in an older adult living with multiple chronic conditions and/or frailty. We may focus on providing evidence-based care for individual medical conditions while neglecting the often practical interventions that can help an older person age in place by focusing on what matters, supporting safe mobility, addressing cognition and mood, and optimizing medications.¹⁸

The vision of the VA as the largest AFHS in America is urgently needed; nearly half of the veteran population is aged 65 ≥ years, compared with 16% of the general population.¹⁹ Building on the VA’s legacy of creativity and innovation in geriatrics, and the VA’s goal of being a high reliability organization, becoming an AFHS will ensure that for that older veteran stepping off that elevator there is no wrong floor, and no wrong door to receive the Age-Friendly care he deserves and that we all hope for as we age.^1,5,19,20

Acknowledgments

This material is the result of work supported with resources and the use of facilities at the Veterans Affairs Boston Healthcare System and the New England Geriatric Research Education and Clinical Center. 

One morning I stepped into the elevator in the lobby of the US Department of Veterans Affairs (VA) medical center where I work, holding a cup of coffee, joining another staffer, a middle-aged man, wearing a veteran’s pin on his employee badge. An older veteran slowly approached the elevator doors, shuffling with each step, and since he was at the front of the elevator, he cheerfully bellowed “Which floor?” as he offered to push the button for us.

“What’s on 12?” he asked in a jovial voice. I smiled. “Aging research,” referring to the Geriatrics Research Education and Clinical Center where I work.¹

“I definitely need that—I forgot where I’m going!” he joked, his fingers hovering over the elevator buttons.

As we reached his floor, the doors opened, he waved with a smile and unsteadily made his way out of the elevator and down the hall to his appointment. As the elevator doors closed behind him, the other staffer turned to me and said with a shrug, “That’ll be me one day,” as he got off at the next floor.

When I got off the elevator and walked toward my office, I reflected on the care that I as a geriatrician and we at the VA hope to provide to aging veterans, now and in the future: Age-Friendly care. Age-Friendly means the compassionate care that we want for those who have served our country, for our loved ones, and for ourselves as we age. Age-Friendly means person-centered, evidence-based care that as we grow older will help us to address challenges that may come with older age, such as falls, cognitive impairment, and polypharmacy. Too often the health care system remains focused on the chief concern or on a clinician’s specialty and may not focus on those important areas where we can potentially intervene to support aging veterans.

The VA has set a goal to become the largest Age-Friendly Health System (AFHS) in the country.² Led by the Institute for Healthcare Improvement and funded by the John A. Hartford Foundation, the Age-Friendly Health Systems Initiative aims to help clinicians and care settings “follow an essential set of evidence-based practices; cause no harm; and align with what matters to the older adult and their family caregivers.”³ An AFHS cares for older adults with attention to the 4Ms—What Matters, Mobility, Mentation, and Medications.⁴ Specifically, in an AFHS, older adults are asked what matters to them so we can align their health care with their goals; clinicians evaluate veterans for safe mobility and fall risk reduction, cognitive impairment and mood disorders, and identify and avoid high-risk medications.⁵ In an AFHS, the 4Ms are practiced as a set, reliably, across settings, so that there should be no wrong door or wrong floor for an older veteran to receive Age-Friendly care within the VA health care system.⁶

Too often our health care system and health professions education have left clinicians unprepared to care for older adults using an Age-Friendly framework; rather, we have been trained in problem-based or disease-based care that can miss the forest for the trees in an older adult living with multiple chronic conditions and/or frailty. We may focus on providing evidence-based care for individual medical conditions while neglecting the often practical interventions that can help an older person age in place by focusing on what matters, supporting safe mobility, addressing cognition and mood, and optimizing medications.¹⁸

The vision of the VA as the largest AFHS in America is urgently needed; nearly half of the veteran population is aged 65 ≥ years, compared with 16% of the general population.¹⁹ Building on the VA’s legacy of creativity and innovation in geriatrics, and the VA’s goal of being a high reliability organization, becoming an AFHS will ensure that for that older veteran stepping off that elevator there is no wrong floor, and no wrong door to receive the Age-Friendly care he deserves and that we all hope for as we age.^1,5,19,20

Acknowledgments

This material is the result of work supported with resources and the use of facilities at the Veterans Affairs Boston Healthcare System and the New England Geriatric Research Education and Clinical Center. 

One morning I stepped into the elevator in the lobby of the US Department of Veterans Affairs (VA) medical center where I work, holding a cup of coffee, joining another staffer, a middle-aged man, wearing a veteran’s pin on his employee badge. An older veteran slowly approached the elevator doors, shuffling with each step, and since he was at the front of the elevator, he cheerfully bellowed “Which floor?” as he offered to push the button for us.

“What’s on 12?” he asked in a jovial voice. I smiled. “Aging research,” referring to the Geriatrics Research Education and Clinical Center where I work.¹

“I definitely need that—I forgot where I’m going!” he joked, his fingers hovering over the elevator buttons.

As we reached his floor, the doors opened, he waved with a smile and unsteadily made his way out of the elevator and down the hall to his appointment. As the elevator doors closed behind him, the other staffer turned to me and said with a shrug, “That’ll be me one day,” as he got off at the next floor.

When I got off the elevator and walked toward my office, I reflected on the care that I as a geriatrician and we at the VA hope to provide to aging veterans, now and in the future: Age-Friendly care. Age-Friendly means the compassionate care that we want for those who have served our country, for our loved ones, and for ourselves as we age. Age-Friendly means person-centered, evidence-based care that as we grow older will help us to address challenges that may come with older age, such as falls, cognitive impairment, and polypharmacy. Too often the health care system remains focused on the chief concern or on a clinician’s specialty and may not focus on those important areas where we can potentially intervene to support aging veterans.

The VA has set a goal to become the largest Age-Friendly Health System (AFHS) in the country.² Led by the Institute for Healthcare Improvement and funded by the John A. Hartford Foundation, the Age-Friendly Health Systems Initiative aims to help clinicians and care settings “follow an essential set of evidence-based practices; cause no harm; and align with what matters to the older adult and their family caregivers.”³ An AFHS cares for older adults with attention to the 4Ms—What Matters, Mobility, Mentation, and Medications.⁴ Specifically, in an AFHS, older adults are asked what matters to them so we can align their health care with their goals; clinicians evaluate veterans for safe mobility and fall risk reduction, cognitive impairment and mood disorders, and identify and avoid high-risk medications.⁵ In an AFHS, the 4Ms are practiced as a set, reliably, across settings, so that there should be no wrong door or wrong floor for an older veteran to receive Age-Friendly care within the VA health care system.⁶

Too often our health care system and health professions education have left clinicians unprepared to care for older adults using an Age-Friendly framework; rather, we have been trained in problem-based or disease-based care that can miss the forest for the trees in an older adult living with multiple chronic conditions and/or frailty. We may focus on providing evidence-based care for individual medical conditions while neglecting the often practical interventions that can help an older person age in place by focusing on what matters, supporting safe mobility, addressing cognition and mood, and optimizing medications.¹⁸

The vision of the VA as the largest AFHS in America is urgently needed; nearly half of the veteran population is aged 65 ≥ years, compared with 16% of the general population.¹⁹ Building on the VA’s legacy of creativity and innovation in geriatrics, and the VA’s goal of being a high reliability organization, becoming an AFHS will ensure that for that older veteran stepping off that elevator there is no wrong floor, and no wrong door to receive the Age-Friendly care he deserves and that we all hope for as we age.^1,5,19,20

Acknowledgments

This material is the result of work supported with resources and the use of facilities at the Veterans Affairs Boston Healthcare System and the New England Geriatric Research Education and Clinical Center. 

Tuba City Regional Health Care Corporation (TCRHCC) is located on the Navajo Reservation in northeastern Arizona and provides medical coverage to a 6000-square-mile area, serving more than 33,000 residents of the Navajo, Hopi, and San Juan Southern Paiute tribes.^1,2 In 2021, there were 334,497 outpatient visits. TCRHCC departments involved in prescribing outpatient antibiotics include the emergency, internal medicine, family medicine, pediatrics, dentistry, surgery, podiatry, obstetrics and gynecology, and midwifery.

Antimicrobial resistance is one of the largest public health threats, causing an estimated 2 million infections and 23,000 deaths every year in the United States.³ This can lead to increased health care costs, morbidity, and mortality. A large, modifiable risk factor is the inappropriate prescribing of antibiotics: An estimated half of all outpatient antibiotics prescribed may be inappropriate in some manner, such as antibiotic choice, dosing, or duration. In addition, at least 30% of US antibiotic prescriptions are unnecessary, leading to significant overuse.³ As such, antimicrobial stewardship is a cornerstone of improving antibiotic use, patient care, and safety.

The goals of antimicrobial stewardship are to measure antimicrobial prescribing, improve clinician prescribing, minimize misdiagnosis or delayed diagnoses, and ensure the right drug, dose, and duration are selected when antimicrobial therapy is appropriate.³ The Centers for Disease Control and Prevention recommends 4 core elements of outpatient antimicrobial stewardship: commitment, action for policy and practice, tracking and reporting, and education and expertise.³ This study focuses on the pillars of action for policy and practice and tracking and reporting.

Methods

The study objectives were not designed to achieve statistical power. A retrospective chart review was performed for patients of any age who were seen in an ambulatory care setting at TCRHCC from August 1, 2020, to August 1, 2021, with a visit diagnosis included in the outpatient antimicrobial prescribing guidelines.^4,5 A random sample of 10% of charts of each diagnosis code was used for analysis. An Excel spreadsheet with all patient charts, separated by diagnosis code, was created. Each chart was then assigned a number, and the Excel function RAND was used to select a random number from the pool. This was continued until 10% of each category, or at least 1 chart from diagnosis code categories with less than 10 total charts available, were selected.

Inclusion criteria were patients seen in ambulatory clinics or the emergency department, an infectious disease diagnosis addressed in the facility guidelines, diagnosis and treatment occurred between August 1, 2020, and August 1, 2021, and the patient was discharged home after the visit. Exclusion criteria were patients who required inpatient admission, patient visits to the clinic established solely for COVID-19 vaccination or testing as no other care was ever provided at this location, patients who refused treatment, patients who failed empiric therapy and required treatment adjustments, or patients who were initially treated and received an antibiotic prescription at a facility outside the TCRHCC system.

After chart review and analysis were completed, a prescriber survey and educational intervention were performed from March 2, 2022, to March 31, 2022. This consisted of an anonymous survey to gather demographic data and prescribing habits pre-education, a short educational brief on the existence, location, and recommended use of the outpatient antimicrobial prescribing guidelines, and a posteducation survey to assess knowledge of the guidelines and willingness to adhere to them after the educational intervention.

Results

We reviewed 8779 patient records. A random sample of 10% of the records of each diagnosis code was taken and 876 charts were reviewed. Of the charts reviewed, 351 patients met the inclusion criteria and were included in the analysis. A goal of 90% was established as the target for prescriber adherence for the study based on author consensus for a reasonable goal. Of the 351 evaluated charts, 62 (16.1%) were pediatric patients (aged < 19 years) and 289 (83.9%) were adults (aged ≥ 19 years). Fifty-two (84%) of the pediatric charts and 249 (86%) of the adult charts demonstrated prescribers had appropriately followed guidelines for a combined total of 301 of the 351 charts and an overall adherence rate of 86%. This was 4 points below the established goal of 90%, warranting further investigation. An analysis of prescribers and locations revealed no trends or patterns of nonadherence. A prescriber survey and educational intervention were designed and disseminated to all prescribers at the facility with the approval and assistance of the chief of medicine.

Thirty-nine prescribers responded to the survey. In the pre-educational survey, clinical resources were the most common source of guidance with 36 prescribers (92%) indicating they used them to make an appropriate selection of an antimicrobial; 32 (82%) used personal knowledge, 30 (77%) used culture results, and 24 (62%) used facility guidelines. This was consistent with the posteducational questions: 12 (31%) indicated they were not aware of the facility guidelines before the educational intervention.

Discussion

This study’s objective was to evaluate prescriber adherence to the facility outpatient prescribing guidelines after they were implemented in 2019 and to plan for interventions if necessary. Overall prescriber adherence was high with 86% of the sampled charts adherent. This was below the goal of 90%, so evaluation of the nonadherent charts was warranted for the determination of any patterns to guide the planned interventions with the facility prescribers. However, no trends were identified, so the intervention was designed as a general survey and educational session for all prescribers. Overall prescriber response was positive, with a total of 34 responding prescribers (87%) indicating a willingness to use the guidelines.

Limitations

This is a retrospective observational study performed through chart review that allowed for frequency analysis but did not allow for statistical analysis, so the significance of results cannot be obtained. Additionally, this study was not able to compare rates of adherence before and after the educational intervention, so the effectiveness of the intervention cannot be assessed.

Conclusions

This retrospective observational study’s data demonstrate that prescribers are adhering at a high rate to recommended empiric antimicrobials for outpatient treatment with an 86% adherence rate. Response to educational intervention indicated a larger proportion of prescribers than previously will use the guidelines. However, the impact this will have on appropriate prescribing rates in the future could not be assessed during this study.

Tuba City Regional Health Care Corporation (TCRHCC) is located on the Navajo Reservation in northeastern Arizona and provides medical coverage to a 6000-square-mile area, serving more than 33,000 residents of the Navajo, Hopi, and San Juan Southern Paiute tribes.^1,2 In 2021, there were 334,497 outpatient visits. TCRHCC departments involved in prescribing outpatient antibiotics include the emergency, internal medicine, family medicine, pediatrics, dentistry, surgery, podiatry, obstetrics and gynecology, and midwifery.

Antimicrobial resistance is one of the largest public health threats, causing an estimated 2 million infections and 23,000 deaths every year in the United States.³ This can lead to increased health care costs, morbidity, and mortality. A large, modifiable risk factor is the inappropriate prescribing of antibiotics: An estimated half of all outpatient antibiotics prescribed may be inappropriate in some manner, such as antibiotic choice, dosing, or duration. In addition, at least 30% of US antibiotic prescriptions are unnecessary, leading to significant overuse.³ As such, antimicrobial stewardship is a cornerstone of improving antibiotic use, patient care, and safety.

The goals of antimicrobial stewardship are to measure antimicrobial prescribing, improve clinician prescribing, minimize misdiagnosis or delayed diagnoses, and ensure the right drug, dose, and duration are selected when antimicrobial therapy is appropriate.³ The Centers for Disease Control and Prevention recommends 4 core elements of outpatient antimicrobial stewardship: commitment, action for policy and practice, tracking and reporting, and education and expertise.³ This study focuses on the pillars of action for policy and practice and tracking and reporting.

Methods

The study objectives were not designed to achieve statistical power. A retrospective chart review was performed for patients of any age who were seen in an ambulatory care setting at TCRHCC from August 1, 2020, to August 1, 2021, with a visit diagnosis included in the outpatient antimicrobial prescribing guidelines.^4,5 A random sample of 10% of charts of each diagnosis code was used for analysis. An Excel spreadsheet with all patient charts, separated by diagnosis code, was created. Each chart was then assigned a number, and the Excel function RAND was used to select a random number from the pool. This was continued until 10% of each category, or at least 1 chart from diagnosis code categories with less than 10 total charts available, were selected.

Inclusion criteria were patients seen in ambulatory clinics or the emergency department, an infectious disease diagnosis addressed in the facility guidelines, diagnosis and treatment occurred between August 1, 2020, and August 1, 2021, and the patient was discharged home after the visit. Exclusion criteria were patients who required inpatient admission, patient visits to the clinic established solely for COVID-19 vaccination or testing as no other care was ever provided at this location, patients who refused treatment, patients who failed empiric therapy and required treatment adjustments, or patients who were initially treated and received an antibiotic prescription at a facility outside the TCRHCC system.

After chart review and analysis were completed, a prescriber survey and educational intervention were performed from March 2, 2022, to March 31, 2022. This consisted of an anonymous survey to gather demographic data and prescribing habits pre-education, a short educational brief on the existence, location, and recommended use of the outpatient antimicrobial prescribing guidelines, and a posteducation survey to assess knowledge of the guidelines and willingness to adhere to them after the educational intervention.

Results

We reviewed 8779 patient records. A random sample of 10% of the records of each diagnosis code was taken and 876 charts were reviewed. Of the charts reviewed, 351 patients met the inclusion criteria and were included in the analysis. A goal of 90% was established as the target for prescriber adherence for the study based on author consensus for a reasonable goal. Of the 351 evaluated charts, 62 (16.1%) were pediatric patients (aged < 19 years) and 289 (83.9%) were adults (aged ≥ 19 years). Fifty-two (84%) of the pediatric charts and 249 (86%) of the adult charts demonstrated prescribers had appropriately followed guidelines for a combined total of 301 of the 351 charts and an overall adherence rate of 86%. This was 4 points below the established goal of 90%, warranting further investigation. An analysis of prescribers and locations revealed no trends or patterns of nonadherence. A prescriber survey and educational intervention were designed and disseminated to all prescribers at the facility with the approval and assistance of the chief of medicine.

Thirty-nine prescribers responded to the survey. In the pre-educational survey, clinical resources were the most common source of guidance with 36 prescribers (92%) indicating they used them to make an appropriate selection of an antimicrobial; 32 (82%) used personal knowledge, 30 (77%) used culture results, and 24 (62%) used facility guidelines. This was consistent with the posteducational questions: 12 (31%) indicated they were not aware of the facility guidelines before the educational intervention.

Discussion

This study’s objective was to evaluate prescriber adherence to the facility outpatient prescribing guidelines after they were implemented in 2019 and to plan for interventions if necessary. Overall prescriber adherence was high with 86% of the sampled charts adherent. This was below the goal of 90%, so evaluation of the nonadherent charts was warranted for the determination of any patterns to guide the planned interventions with the facility prescribers. However, no trends were identified, so the intervention was designed as a general survey and educational session for all prescribers. Overall prescriber response was positive, with a total of 34 responding prescribers (87%) indicating a willingness to use the guidelines.

Limitations

This is a retrospective observational study performed through chart review that allowed for frequency analysis but did not allow for statistical analysis, so the significance of results cannot be obtained. Additionally, this study was not able to compare rates of adherence before and after the educational intervention, so the effectiveness of the intervention cannot be assessed.

Conclusions

This retrospective observational study’s data demonstrate that prescribers are adhering at a high rate to recommended empiric antimicrobials for outpatient treatment with an 86% adherence rate. Response to educational intervention indicated a larger proportion of prescribers than previously will use the guidelines. However, the impact this will have on appropriate prescribing rates in the future could not be assessed during this study.

Tuba City Regional Health Care Corporation (TCRHCC) is located on the Navajo Reservation in northeastern Arizona and provides medical coverage to a 6000-square-mile area, serving more than 33,000 residents of the Navajo, Hopi, and San Juan Southern Paiute tribes.^1,2 In 2021, there were 334,497 outpatient visits. TCRHCC departments involved in prescribing outpatient antibiotics include the emergency, internal medicine, family medicine, pediatrics, dentistry, surgery, podiatry, obstetrics and gynecology, and midwifery.

Antimicrobial resistance is one of the largest public health threats, causing an estimated 2 million infections and 23,000 deaths every year in the United States.³ This can lead to increased health care costs, morbidity, and mortality. A large, modifiable risk factor is the inappropriate prescribing of antibiotics: An estimated half of all outpatient antibiotics prescribed may be inappropriate in some manner, such as antibiotic choice, dosing, or duration. In addition, at least 30% of US antibiotic prescriptions are unnecessary, leading to significant overuse.³ As such, antimicrobial stewardship is a cornerstone of improving antibiotic use, patient care, and safety.

The goals of antimicrobial stewardship are to measure antimicrobial prescribing, improve clinician prescribing, minimize misdiagnosis or delayed diagnoses, and ensure the right drug, dose, and duration are selected when antimicrobial therapy is appropriate.³ The Centers for Disease Control and Prevention recommends 4 core elements of outpatient antimicrobial stewardship: commitment, action for policy and practice, tracking and reporting, and education and expertise.³ This study focuses on the pillars of action for policy and practice and tracking and reporting.

Methods

The study objectives were not designed to achieve statistical power. A retrospective chart review was performed for patients of any age who were seen in an ambulatory care setting at TCRHCC from August 1, 2020, to August 1, 2021, with a visit diagnosis included in the outpatient antimicrobial prescribing guidelines.^4,5 A random sample of 10% of charts of each diagnosis code was used for analysis. An Excel spreadsheet with all patient charts, separated by diagnosis code, was created. Each chart was then assigned a number, and the Excel function RAND was used to select a random number from the pool. This was continued until 10% of each category, or at least 1 chart from diagnosis code categories with less than 10 total charts available, were selected.

Inclusion criteria were patients seen in ambulatory clinics or the emergency department, an infectious disease diagnosis addressed in the facility guidelines, diagnosis and treatment occurred between August 1, 2020, and August 1, 2021, and the patient was discharged home after the visit. Exclusion criteria were patients who required inpatient admission, patient visits to the clinic established solely for COVID-19 vaccination or testing as no other care was ever provided at this location, patients who refused treatment, patients who failed empiric therapy and required treatment adjustments, or patients who were initially treated and received an antibiotic prescription at a facility outside the TCRHCC system.

After chart review and analysis were completed, a prescriber survey and educational intervention were performed from March 2, 2022, to March 31, 2022. This consisted of an anonymous survey to gather demographic data and prescribing habits pre-education, a short educational brief on the existence, location, and recommended use of the outpatient antimicrobial prescribing guidelines, and a posteducation survey to assess knowledge of the guidelines and willingness to adhere to them after the educational intervention.

Results

We reviewed 8779 patient records. A random sample of 10% of the records of each diagnosis code was taken and 876 charts were reviewed. Of the charts reviewed, 351 patients met the inclusion criteria and were included in the analysis. A goal of 90% was established as the target for prescriber adherence for the study based on author consensus for a reasonable goal. Of the 351 evaluated charts, 62 (16.1%) were pediatric patients (aged < 19 years) and 289 (83.9%) were adults (aged ≥ 19 years). Fifty-two (84%) of the pediatric charts and 249 (86%) of the adult charts demonstrated prescribers had appropriately followed guidelines for a combined total of 301 of the 351 charts and an overall adherence rate of 86%. This was 4 points below the established goal of 90%, warranting further investigation. An analysis of prescribers and locations revealed no trends or patterns of nonadherence. A prescriber survey and educational intervention were designed and disseminated to all prescribers at the facility with the approval and assistance of the chief of medicine.

Thirty-nine prescribers responded to the survey. In the pre-educational survey, clinical resources were the most common source of guidance with 36 prescribers (92%) indicating they used them to make an appropriate selection of an antimicrobial; 32 (82%) used personal knowledge, 30 (77%) used culture results, and 24 (62%) used facility guidelines. This was consistent with the posteducational questions: 12 (31%) indicated they were not aware of the facility guidelines before the educational intervention.

Discussion

This study’s objective was to evaluate prescriber adherence to the facility outpatient prescribing guidelines after they were implemented in 2019 and to plan for interventions if necessary. Overall prescriber adherence was high with 86% of the sampled charts adherent. This was below the goal of 90%, so evaluation of the nonadherent charts was warranted for the determination of any patterns to guide the planned interventions with the facility prescribers. However, no trends were identified, so the intervention was designed as a general survey and educational session for all prescribers. Overall prescriber response was positive, with a total of 34 responding prescribers (87%) indicating a willingness to use the guidelines.

Limitations

This is a retrospective observational study performed through chart review that allowed for frequency analysis but did not allow for statistical analysis, so the significance of results cannot be obtained. Additionally, this study was not able to compare rates of adherence before and after the educational intervention, so the effectiveness of the intervention cannot be assessed.

Conclusions

This retrospective observational study’s data demonstrate that prescribers are adhering at a high rate to recommended empiric antimicrobials for outpatient treatment with an 86% adherence rate. Response to educational intervention indicated a larger proportion of prescribers than previously will use the guidelines. However, the impact this will have on appropriate prescribing rates in the future could not be assessed during this study.

As the prevalence of obstructive sleep apnea (OSA) has steadily increased in the United States, so has the awareness of central sleep apnea (CSA). The hallmark of CSA is transient cessation of airflow during sleep due to a lack of respiratory effort triggered by the brain. This is in contrast to OSA, in which there is absence of airflow despite continued ventilatory effort due to physical airflow obstruction. The gold standard for the diagnosis and optimal treatment assessment of CSA is inlaboratory polysomnography (PSG) with esophageal manometry, but in practice, respiratory effort is generally estimated through oronasal flow and respiratory inductance plethysmography bands placed on the chest and abdomen during PSG.

Background

The literature has demonstrated a higher prevalence of moderate-to-severe OSA in the general population compared with that of CSA. While OSA is associated with worse clinical outcomes, more evidence is needed on the long-term clinical impact and optimal treatment strategies for CSA.¹ CSA is overrepresented among certain clinical populations. CSA is not frequently diagnosed in the active-duty population, but is increasing in the veteran population, especially in those with heart failure (HF), stroke, neuromuscular disorders, and opioid use. It is associated with increased admissions related to comorbid cardiovascular disorders and to an increased risk of death.^2-4 The clinical concerns with CSA parallel those of OSA. The absence of respiration (apneas and hypopneas due to lack of effort) results in sympathetic surge, compromise of oxygenation and ventilation, sleep fragmentation, and elevation in blood pressure. Symptoms such as excessive daytime sleepiness, morning headaches, witnessed apneas, and nocturnal arrhythmias are shared between the 2 disorders.

Ventilatory instability is the most widely accepted mechanism leading to CSA in patients. Loop gain is the concept used to explain ventilatory control. This feedback loop is influenced by controller gain (primarily represented by central and peripheral chemoreceptors causing changes in ventilation due to PaCO₂ [partial pressure of CO₂ in arterial blood] fluctuations), plant gain (includes lungs and respiratory muscles and their ability to eliminate CO₂), and circulation time (feedback between controller and plant).⁵

High loop gain and narrow CO₂ reserve contribute to ventilatory instability in CSA.⁶ Those with high loop gain have increased sensitivity to changes in CO₂. These patients tend to overbreathe in response to smaller increases in PaCO₂ compared with those with low loop gain. Once the PaCO₂ falls below an individual’s apneic threshold (AT), an apnea will occur.⁷ The brainstem then pauses ventilation to allow the PaCO₂ to rise back above the AT. CSAs also can occur in healthy individuals as they transition from wakefulness into non–rapid eye movement (REM) sleep in a phenomenon called sleep state oscillation, with a mechanism that is similar to hyperventilation-induced CSAs described earlier.

Primary CSA has been defined in the International Classification of Sleep Disorders 3rd edition (ICSD-3) with the following criteria: (1) diagnostic PSG with ≥ 5 events per hour of CSAs and/or central hypopneas per hour of sleep; the number of CSAs and/or central hypopneas is > 50% of the total number of apneas and hypopneas; and there is no evidence of Cheyne-Stokes breathing (CSB); (2) the patient reports sleepiness, awakening with shortness of breath, snoring, witnessed apneas, or insomnia; (3) there is no evidence of nocturnal hypoventilation; and (4) the disorder is not better explained by another medical use, substance use disorder (SUD), or other current sleep, medical, or neurologic disorder.⁸

A systematic clinical approach should be used to identify and treat CSA (Figure).^6,7

Nonhypercapnic CSA

Heart Failure–Induced CSA

The leading medical diagnosis causing CSA is congestive HF (CHF), and there is a correlation between HF severity and presence of CSA. In patients with stable CHF with HF reduced ejection fraction (HFrEF), CSA is highly prevalent, occurring in 25% to 40% of patients.⁹ In contrast to other subtypes of CSA where literature regarding prognosis is lacking, the literature is clear that patients with HFrEF with CSA have a worse prognosis, with increased risk of death independent of the severity of HF. This may be the result of CSA promoting malignant ventricular arrhythmias. The prevalence of CSA in HF with preserved ejection fraction (HFpEF) is about 18% to 30%.^10,11

A significant reduction in cardiac output results in circulatory delay between the lungs and chemoreceptors that produces CSB periodic breathing, which is characteristic of the most recognized form of CSA. Per the ICSD-3, CSA with CSB requires the following 4 findings: (1) PSG reveals ≥ 5 CSAs and/or central hypopneas per hour of sleep; there are at least 3 consecutive CSAs and/or central hypopneas separated by crescendo-decrescendo breathing with a cycle length of at least 40 seconds (ie, CSB pattern), and the number of CSAs and/or central hypopneas is > 50% of the total number of apneas and hypopneas; (2) the patient reports sleepiness, awakening with shortness of breath, snoring, witnessed apneas, or insomnia; (3) the breathing pattern is associated with atrial fibrillation/flutter, CHF, or a neurologic disorder; and (4) the disorder is not better explained by another current sleep disorder, medication use (eg, opioids), or SUD.⁸

Treatment of HF-induced CSA begins with guideline-based medical management with the goal of reducing pulmonary capillary wedge pressure or increasing left ventricular ejection fraction through means that may include cardiac resynchronization therapy or left ventricular assist devices, when clinically indicated. If medical optimization is not sufficient, the next step is continuous positive airway pressure (CPAP or PAP), followed by adaptive servo-ventilation (ASV) if the apnea-hypopnea index (AHI) remains > 15 events per hour and is clinically indicated.

ASV is a second-line PAP therapy modality that uses proprietary algorithms to provide variable amounts of pressure that alternate between expiratory and inspiratory phases of the respiratory cycle in combination with physician-set or automatic backup respiratory rate designed to stabilize ventilation in patients with CSA and CSB. The inability to adjust tidal volume, potentially resulting in insufficient tidal volumes or ventilation, results in the contraindication for its use in patients with CSA with comorbid conditions that may result in hypercapnic respiratory failure. These conditions include chronic hypoventilation in obesity hypoventilation syndrome (OHS), moderate-to-severe chronic obstructive pulmonary disease, chronic elevation of PaCO₂ on arterial blood gas > 45 mm Hg, and restrictive thoracic or neuromuscular disease.¹²

Although ASV is more effective in normalizing AHI in patients with HF and CSA than is CPAP therapy, the clinical indications for ASV in the setting of HFrEF changed drastically with the publication of the landmark SERVE-HF trial, which investigated the effects of adding ASV to guideline-based medical management on survival and cardiovascular outcomes in patients with HFrEF and predominant CSA.¹³ The study did not show a difference between the ASV and control groups for the primary endpoint: a composite of time to first event of death from any cause, lifesaving cardiovascular intervention (transplantation, implantation of a long-term ventricular assist device, resuscitation after sudden cardiac arrest, or appropriate lifesaving shock), or unplanned hospitalization for worsening HF. However, the study showed a statistically and clinically significant increased risk of all-cause and cardiovascular mortality in the ASV group compared with the control group.¹³ A possible explanation for the increased all-cause and cardiovascular mortality is that CSA potentially serves a protective mechanism that when eliminated results in deleterious clinical outcomes. This resulted in significant changes in the treatment algorithm for HF-induced CSA with left ventricular ejection fraction of at least 45% becoming the cutoff for therapeutic decisions.

Treatment-Emergent CSA

Treatment-emergent CSA (TECSA, also known as complex sleep apnea) has been defined by the ICSD-3 by the following criteria: (1) diagnostic PSG with ≥ 5 events per hour of predominantly obstructive events; (2) resolution of obstructive events with PAP without a backup rate and CSA index (CAI) ≥ 5 per hour with central events ≥ 50% of the AHI; and (3) CSA not better explained by another disorder.⁸ Patients with TECSA can be further classified into those who have transient events that resolve within weeks to months, those with persistent events, and those with delayed events that may develop weeks to months after initiating PAP therapy.¹⁴

PAP treatment can decrease the PaCO₂ below the AT due to removal of flow limitation in previously obstructed upper airways, resulting in TECSA.^15,16 PAP therapy has not been the only treatment where new CSA has been identified on initiation. A 2021 systematic review identified patients who developed new-onset CSA with mandibular advancement device (MAD), hypoglossal nerve stimulator, tongue protrusion device, and nasal expiratory PAP device use, as well as after tracheostomy, maxillofacial surgery, and other surgeries, such as nasal and uvulopalatopharyngoplasty.¹⁷

The prevalence of TECSA has been noted to range between 0.6% and 20.3%, but Nigam and colleagues estimated a prevalence of 8.4% in their systematic review.^11,14 The variability in prevalence between studies could be due to differences in study design (retrospective vs prospective vs cross-sectional), diagnostic and inclusion criteria, patient population, and type of study used (full-night vs split-night vs both).^18,19 Risk factors for TECSA include male sex; older age; lower body mass index; higher baseline AHI, CAI, and arousal index; chronic medical issues such as CHF and coronary artery disease; opioid use; higher CPAP settings; excessive mask leak; and bilevel PAP (BiPAP) use.²⁰ Identifying these risk factors is important, as patients with TECSA are at higher risk of discontinuing therapy and of developing PAP intolerance.^15,20

Most patients with TECSA can continue CPAP therapy with resolution of events over weeks to months, but treatment of comorbid conditions should be optimized as they could be contributing factors. Zeineddine and colleagues recommend continuation of CPAP for 3 months if the patient has minor or no symptoms.¹⁹ A 2018 systematic review noted that 14.3% to 46.2% of TECSA patients will have persistent TECSA and some will develop TECSA after at least 1 month of PAP therapy.¹⁴ For these patients and those with severe symptoms in spite of therapy, a switch to BiPAP spontaneous/timed (BiPAP-S/T) or ASV should be considered, if not contraindicated based on comorbidities.²¹ Medications such as acetazolamide, oxygen therapy, and CO₂ supplementation have also been discussed as alternative treatments, but these options should not be first-line therapies and should be used on a case-by-case basis as adjuncts to PAP therapy.^16,17

Altitude-Induced CSA

Also known as CSA due to high-altitude periodic breathing (CSA-HAPB), this form of CSA occurs in nearly all lowlanders at altitudes above 3000 m, with severity increasing with altitude.¹⁵ The exact altitude at which it occurs varies based on an individual’s physiology. CSA-HAPB occurs in response to the low barometric pressure at altitude, combined with stable fraction of oxygen, resulting in decreased inspired partial pressure of oxygen and hypoxia. The normal physiologic response to hypoxia is increased ventilation, which can cause hypocapnia, suppressing respiratory drive and resulting in CSAs. The instability of the respiratory response results in cyclical CSAs followed by hyperventilation. This periodic breathing then causes arousals from sleep, driving further sleep fragmentation and exacerbation of baseline desaturation and instability in the cyclical respiratory response. There is individual variability in hypoxic chemoresponsiveness (loop gain). Compensatory mechanisms are most robust when an individual routinely dwells at high altitude, resulting in acclimatization, rather than traveling there for a brief stay. Genetics and cardiac output also contribute to the effectiveness of compensation to altitude.

CSA-HAPB is defined by the following ICSD-3 criteria: (1) Recent ascent to a high altitude (typically ≥ 2500 m, although some individuals may exhibit the disorder at altitudes as low as 1500 m); (2) the patient reports sleepiness, awakening with shortness of breath, snoring, witnessed apneas, or insomnia; (3) symptoms are clinically attributable to HAPB, or PSG, if performed, reveals recurrent CSAs or hypopneas primarily during non-REM sleep at a frequency of ≥ 5 events per hour; (4) the disorder is not better explained by another current sleep disorder, medical or neurological disorder, medication use (eg, narcotics), or SUD.⁸

Treatment options to improve nocturnal oxygen saturation and reduce or eliminate CSA-HAPB in nonacclimatized individuals include oxygen-enriched air, acetazolamide, or combination treatment with acetazolamide and automatic PAP (APAP).²² A meta-analysis looking at the effectiveness of acetazolamide in 8 different randomized controlled trials demonstrated that a dose of 250 mg per day was effective in improving sleep apnea at altitude as measured by a decrease in AHI, decrease in percentage of periodic breathing, and increasing oxygenation during sleep.¹⁵ The question of superiority of combined acetazolamide with APAP to placebo with APAP in treatment of high-altitude OSA was addressed in a randomized double-blind, placebo-controlled trial. The results showed that combined APAP (5-15 cm of water pressure) and acetazolamide (250 mg morning, 500 mg evening) decreased the AHI to normal range, whereas central events persisted in the APAP and placebo group.²³ In addition, Latshang and colleagues have demonstrated that ASV may not be as efficacious for controlling CSA-HAPB in nonacclimatized individuals compared with oxygen therapy and suggested that further research is warranted examining if ASV device algorithm adjustment improves efficacy of this therapeutic option.²⁴

Comorbidity-Induced CSA

Several medical conditions may be associated with CSA, including chronic kidney disease (CKD), pulmonary hypertension, acromegaly, and hypothyroidism. The common pathophysiologic link is that these disorders may result in alteration of ventilatory responses to CO₂, ultimately resulting in CSA.

As many as 10% of patients with CKD may experience CSA.^25,26 The complications encountered in CKD include fluid overload with pulmonary edema, chronic metabolic acidosis, and anemia. These can provoke hyperventilation in addition to poor sleep quality, triggering arousals that further drive CSA in these patients. Additional risk factors for CSA in this population include atrial fibrillation and cardiac dysfunction. Clinical interventions that have demonstrated reduction in CSA include hemodialysis at night vs daytime and using bicarbonate buffer vs acetate for hemodialysis ^22-24,26-29

Hypersecretion of growth hormone in acromegaly also results in hyperventilation contributing to CSA. While medical and surgical management of acromegaly results in a reduction in OSA, there is limited evidence on the outcome of the CSA after these interventions.

Hypothyroidism and CSA both present with similar symptoms of fatigue, daytime sleepiness, depression, and headaches. Studies suggest that respiratory muscle fatigue and decreased ventilatory response to hypercapnia and hypoxia contribute to apnea in this population. In one study, 27% of hypothyroid patients had a blunted response to hypercapnia, and 34% suffered from a blunted response to hypoxia. The same study showed universal reversal of the impairment following thyroid replacement therapy and return to euthyroid state.³⁰ Similarly, multiple studies have shown reversal of respiratory muscle fatigue after initiation of thyroid replacement.^30-32 Assessing thyroid function is an appropriate initial step during any sleep-disordered breathing workup, as it is a reversible cause of apnea. Up to 2.4% of patients presenting for PSG (and diagnosed with OSA) are found to have undiagnosed hypothyroidism.^32,33 In a military population, treatment of a secondary cause of CSA, such as hypothyroidism, could remove some administrative burden as well as improve service members’ quality of life.

If CSA persists despite previous treatment strategies, then clinicians should focus on the optimization of treatment for comorbid conditions. If that does not resolve CSA, CPAP should be used when AHI remains above 15 events per hour or ASV can be used.

Idiopathic CSA

There are limited data on the pathophysiology and prevalence of idiopathic CSA. In most cases it is hypocapnic CSA, which occurs after an arousal from sleep causing hyperventilation that causes hypocapnia below the apnea threshold similar to CSA-HAPB. Therapeutic options based on addressing underlying pathophysiology include increasing CO₂ by inhalation or addition of dead space. Additional therapeutic options to reduce the arousals and CSAs include hypnotics, such as zolpidem and acetazolamide, but these should be administered only with close clinical monitoring. If symptoms continue, CPAP or ASV may be trialed; however, limited clinical evidence of efficacy exists.¹⁵

For patients with moderate-to-severe CSA, an additional treatment option includes an implantable device (eg, Zoll remede¯), which stimulates the phrenic nerve to move the diaphragm and restore normal breathing. This device is not indicated for those with OSA. Based on data submitted to the US Food and Drug Administration, AHI is reduced by ≥ 50% in 51% of patients with the implanted device and by 11% in patients without the device. Five-year follow-up data show sustained improvements.³⁴

Hypercapnic CSA

CSA due to a medication or substance requires the following criteria: (1) the patient is taking an opioid or other respiratory depressant; (2) the patient reports sleepiness, awakening with shortness of breath, snoring, witnessed apneas, or insomnia (difficulty initiating or maintaining sleep, frequent awakenings, or nonrestorative sleep); (3) PSG reveals ≥ 5 CSAs and/or central hypopneas per hour of sleep; the number of CSAs and/or central hypopneas is > 50% of the total number of apneas and hypopneas; and there is no evidence of CSB; and (4) the disorder is not better explained by another current sleep disorder.⁸

Drugs that affect the respiratory centers, such as opiates and opioids, γ aminobutyric acid (GABA) type A and B receptor agonists, and P2Y(12) receptor antagonists such as ticagrelor, may result in alterations in ventilatory drive in the central nervous system respiratory centers, resulting in CSA.

Opioids are prescribed either for chronic pain or to treat opiate addiction with methadone, resulting in about one-third of chronic opioid users having some form of CSA.³⁵ CSA may be seen after opioids have been used for at least 2 months. A dose-dependent effect exists with high doses of opioids, typically resulting in hypoventilation, hypercapnia, and hypoxemia with ataxic or erratic breathing and a periodic breathing pattern similar to those described in CSA-HAPB or idiopathic CSA. About 14% to 60% of methadone patients also demonstrate CSA or ataxic breathing.^35,36

Benzodiazepines (GABA-A receptor agonists) and baclofen (a GABA-B receptor agonist) depress central ventilatory drive, blunt the response to hypoxia and hypercapnia, leading to CSAs, and increase risk for OSA by increasing upper airway obstruction through reduction in tone. Use of these medications with antidepressants or opioids further exacerbates this response.

Unlike the other medications previously described, ticagrelor, a first-line dual antiplatelet therapy medication indicated for acute coronary syndrome treatment, actually increases the activity of the respiratory centers but may result in CSA.

First-line treatment, if possible, is reduction in medication dose or complete withdrawal. Additional treatment options include PAP therapies: CPAP, BiPAP, ASV, and oxygen therapy with or without PAP.^37,38 The literature has demonstrated that for the treatment of opioid-associated CSA, ASV (in cases of normocapnia) and noninvasive ventilation (NIV)/BiPAP (in cases with hypercapnia or REM sleep hypoventilation) are superior treatment options when compared with conventional CPAP for elimination of respiratory events. CPAP with oxygen therapy and BiPAP with oxygen therapy are more effective than CPAP alone in reducing respiratory events. However, concerns remain that as with CSA in HF, CSA in chronic opioid users may serve as a physiologic protective mechanism to prevent further clinical injury from opioids. Similarly, as in the use of ASV in the SERVE-HF trial, focusing on elimination of respiratory events may prove detrimental. More studies are needed to determine whether reducing the number of CSA events in chronic opioid users is clinically beneficial when other health outcomes, such as cardiovascular, neurocognitive, hospital/intensive care unit admissions, and mortality risks are examined.

Neuromuscular-Induced CSA

CSA also is highly prevalent in neuromuscular conditions, such as amyotrophic lateral sclerosis, Duchenne muscular dystrophy, myotonic dystrophy, advanced multiple sclerosis, and acid maltase deficiency. There is reduced respiratory muscle strength and tone in these disorders, resulting in alveolar hypoventilation with hypercapnia. Given the hypercapnia, NIV/BiPAP is the first-line treatment to improve survival, gas exchange, symptom burden, and quality of life.

Stroke-Induced CSA

Extensive cerebrovascular events commonly precipitate sleep-related breathing disorders. The incidence increases in the acute phase of stroke and decreases 3 to 6 months poststroke; however, incidence also depends on the severity of the stroke.^7,39,40 Stroke also has been shown to be a predictor of CSA (odds ratio, 1.65; 95% CI, 1.50-1.82; P < .001) in a retrospective analysis of a large cohort of US veterans.² The location of the lesion often determines whether normocapnic or hypercapnic CSA will predominate, based on ventilatory instability resulting in normocapnia or reduced ventilatory drive resulting in hypercapnic CSA. PSG results and blood gases direct the treatment options. CSA with normocapnia is treated with ASV, and patients with hypercapnia/REM sleep hypoventilation are treated with NIV/BiPAP.

Conclusions

While much has been learned about CSA in recent decades, more evidence needs to be gathered to determine optimal treatment strategies and the impact on patient prognosis. The identification of CSA can lead to the diagnosis of previously unrecognized medical conditions. With proper diagnosis and treatment, we can optimize clinical management and improve patients’ prognosis and quality of life.

Acknowledgments

The authors thank the librarians of the Franzello Aeromedical Library in particular Sara Craycraft, Catherine Stahl, Kristen Young and Elizabeth Irvine for their support of this publication.

As the prevalence of obstructive sleep apnea (OSA) has steadily increased in the United States, so has the awareness of central sleep apnea (CSA). The hallmark of CSA is transient cessation of airflow during sleep due to a lack of respiratory effort triggered by the brain. This is in contrast to OSA, in which there is absence of airflow despite continued ventilatory effort due to physical airflow obstruction. The gold standard for the diagnosis and optimal treatment assessment of CSA is inlaboratory polysomnography (PSG) with esophageal manometry, but in practice, respiratory effort is generally estimated through oronasal flow and respiratory inductance plethysmography bands placed on the chest and abdomen during PSG.

Background

The literature has demonstrated a higher prevalence of moderate-to-severe OSA in the general population compared with that of CSA. While OSA is associated with worse clinical outcomes, more evidence is needed on the long-term clinical impact and optimal treatment strategies for CSA.¹ CSA is overrepresented among certain clinical populations. CSA is not frequently diagnosed in the active-duty population, but is increasing in the veteran population, especially in those with heart failure (HF), stroke, neuromuscular disorders, and opioid use. It is associated with increased admissions related to comorbid cardiovascular disorders and to an increased risk of death.^2-4 The clinical concerns with CSA parallel those of OSA. The absence of respiration (apneas and hypopneas due to lack of effort) results in sympathetic surge, compromise of oxygenation and ventilation, sleep fragmentation, and elevation in blood pressure. Symptoms such as excessive daytime sleepiness, morning headaches, witnessed apneas, and nocturnal arrhythmias are shared between the 2 disorders.

Ventilatory instability is the most widely accepted mechanism leading to CSA in patients. Loop gain is the concept used to explain ventilatory control. This feedback loop is influenced by controller gain (primarily represented by central and peripheral chemoreceptors causing changes in ventilation due to PaCO₂ [partial pressure of CO₂ in arterial blood] fluctuations), plant gain (includes lungs and respiratory muscles and their ability to eliminate CO₂), and circulation time (feedback between controller and plant).⁵

High loop gain and narrow CO₂ reserve contribute to ventilatory instability in CSA.⁶ Those with high loop gain have increased sensitivity to changes in CO₂. These patients tend to overbreathe in response to smaller increases in PaCO₂ compared with those with low loop gain. Once the PaCO₂ falls below an individual’s apneic threshold (AT), an apnea will occur.⁷ The brainstem then pauses ventilation to allow the PaCO₂ to rise back above the AT. CSAs also can occur in healthy individuals as they transition from wakefulness into non–rapid eye movement (REM) sleep in a phenomenon called sleep state oscillation, with a mechanism that is similar to hyperventilation-induced CSAs described earlier.

Primary CSA has been defined in the International Classification of Sleep Disorders 3rd edition (ICSD-3) with the following criteria: (1) diagnostic PSG with ≥ 5 events per hour of CSAs and/or central hypopneas per hour of sleep; the number of CSAs and/or central hypopneas is > 50% of the total number of apneas and hypopneas; and there is no evidence of Cheyne-Stokes breathing (CSB); (2) the patient reports sleepiness, awakening with shortness of breath, snoring, witnessed apneas, or insomnia; (3) there is no evidence of nocturnal hypoventilation; and (4) the disorder is not better explained by another medical use, substance use disorder (SUD), or other current sleep, medical, or neurologic disorder.⁸

A systematic clinical approach should be used to identify and treat CSA (Figure).^6,7

Nonhypercapnic CSA

Heart Failure–Induced CSA

The leading medical diagnosis causing CSA is congestive HF (CHF), and there is a correlation between HF severity and presence of CSA. In patients with stable CHF with HF reduced ejection fraction (HFrEF), CSA is highly prevalent, occurring in 25% to 40% of patients.⁹ In contrast to other subtypes of CSA where literature regarding prognosis is lacking, the literature is clear that patients with HFrEF with CSA have a worse prognosis, with increased risk of death independent of the severity of HF. This may be the result of CSA promoting malignant ventricular arrhythmias. The prevalence of CSA in HF with preserved ejection fraction (HFpEF) is about 18% to 30%.^10,11

A significant reduction in cardiac output results in circulatory delay between the lungs and chemoreceptors that produces CSB periodic breathing, which is characteristic of the most recognized form of CSA. Per the ICSD-3, CSA with CSB requires the following 4 findings: (1) PSG reveals ≥ 5 CSAs and/or central hypopneas per hour of sleep; there are at least 3 consecutive CSAs and/or central hypopneas separated by crescendo-decrescendo breathing with a cycle length of at least 40 seconds (ie, CSB pattern), and the number of CSAs and/or central hypopneas is > 50% of the total number of apneas and hypopneas; (2) the patient reports sleepiness, awakening with shortness of breath, snoring, witnessed apneas, or insomnia; (3) the breathing pattern is associated with atrial fibrillation/flutter, CHF, or a neurologic disorder; and (4) the disorder is not better explained by another current sleep disorder, medication use (eg, opioids), or SUD.⁸

Treatment of HF-induced CSA begins with guideline-based medical management with the goal of reducing pulmonary capillary wedge pressure or increasing left ventricular ejection fraction through means that may include cardiac resynchronization therapy or left ventricular assist devices, when clinically indicated. If medical optimization is not sufficient, the next step is continuous positive airway pressure (CPAP or PAP), followed by adaptive servo-ventilation (ASV) if the apnea-hypopnea index (AHI) remains > 15 events per hour and is clinically indicated.

ASV is a second-line PAP therapy modality that uses proprietary algorithms to provide variable amounts of pressure that alternate between expiratory and inspiratory phases of the respiratory cycle in combination with physician-set or automatic backup respiratory rate designed to stabilize ventilation in patients with CSA and CSB. The inability to adjust tidal volume, potentially resulting in insufficient tidal volumes or ventilation, results in the contraindication for its use in patients with CSA with comorbid conditions that may result in hypercapnic respiratory failure. These conditions include chronic hypoventilation in obesity hypoventilation syndrome (OHS), moderate-to-severe chronic obstructive pulmonary disease, chronic elevation of PaCO₂ on arterial blood gas > 45 mm Hg, and restrictive thoracic or neuromuscular disease.¹²

Although ASV is more effective in normalizing AHI in patients with HF and CSA than is CPAP therapy, the clinical indications for ASV in the setting of HFrEF changed drastically with the publication of the landmark SERVE-HF trial, which investigated the effects of adding ASV to guideline-based medical management on survival and cardiovascular outcomes in patients with HFrEF and predominant CSA.¹³ The study did not show a difference between the ASV and control groups for the primary endpoint: a composite of time to first event of death from any cause, lifesaving cardiovascular intervention (transplantation, implantation of a long-term ventricular assist device, resuscitation after sudden cardiac arrest, or appropriate lifesaving shock), or unplanned hospitalization for worsening HF. However, the study showed a statistically and clinically significant increased risk of all-cause and cardiovascular mortality in the ASV group compared with the control group.¹³ A possible explanation for the increased all-cause and cardiovascular mortality is that CSA potentially serves a protective mechanism that when eliminated results in deleterious clinical outcomes. This resulted in significant changes in the treatment algorithm for HF-induced CSA with left ventricular ejection fraction of at least 45% becoming the cutoff for therapeutic decisions.

Treatment-Emergent CSA

Treatment-emergent CSA (TECSA, also known as complex sleep apnea) has been defined by the ICSD-3 by the following criteria: (1) diagnostic PSG with ≥ 5 events per hour of predominantly obstructive events; (2) resolution of obstructive events with PAP without a backup rate and CSA index (CAI) ≥ 5 per hour with central events ≥ 50% of the AHI; and (3) CSA not better explained by another disorder.⁸ Patients with TECSA can be further classified into those who have transient events that resolve within weeks to months, those with persistent events, and those with delayed events that may develop weeks to months after initiating PAP therapy.¹⁴

PAP treatment can decrease the PaCO₂ below the AT due to removal of flow limitation in previously obstructed upper airways, resulting in TECSA.^15,16 PAP therapy has not been the only treatment where new CSA has been identified on initiation. A 2021 systematic review identified patients who developed new-onset CSA with mandibular advancement device (MAD), hypoglossal nerve stimulator, tongue protrusion device, and nasal expiratory PAP device use, as well as after tracheostomy, maxillofacial surgery, and other surgeries, such as nasal and uvulopalatopharyngoplasty.¹⁷

The prevalence of TECSA has been noted to range between 0.6% and 20.3%, but Nigam and colleagues estimated a prevalence of 8.4% in their systematic review.^11,14 The variability in prevalence between studies could be due to differences in study design (retrospective vs prospective vs cross-sectional), diagnostic and inclusion criteria, patient population, and type of study used (full-night vs split-night vs both).^18,19 Risk factors for TECSA include male sex; older age; lower body mass index; higher baseline AHI, CAI, and arousal index; chronic medical issues such as CHF and coronary artery disease; opioid use; higher CPAP settings; excessive mask leak; and bilevel PAP (BiPAP) use.²⁰ Identifying these risk factors is important, as patients with TECSA are at higher risk of discontinuing therapy and of developing PAP intolerance.^15,20

Most patients with TECSA can continue CPAP therapy with resolution of events over weeks to months, but treatment of comorbid conditions should be optimized as they could be contributing factors. Zeineddine and colleagues recommend continuation of CPAP for 3 months if the patient has minor or no symptoms.¹⁹ A 2018 systematic review noted that 14.3% to 46.2% of TECSA patients will have persistent TECSA and some will develop TECSA after at least 1 month of PAP therapy.¹⁴ For these patients and those with severe symptoms in spite of therapy, a switch to BiPAP spontaneous/timed (BiPAP-S/T) or ASV should be considered, if not contraindicated based on comorbidities.²¹ Medications such as acetazolamide, oxygen therapy, and CO₂ supplementation have also been discussed as alternative treatments, but these options should not be first-line therapies and should be used on a case-by-case basis as adjuncts to PAP therapy.^16,17

Altitude-Induced CSA

Also known as CSA due to high-altitude periodic breathing (CSA-HAPB), this form of CSA occurs in nearly all lowlanders at altitudes above 3000 m, with severity increasing with altitude.¹⁵ The exact altitude at which it occurs varies based on an individual’s physiology. CSA-HAPB occurs in response to the low barometric pressure at altitude, combined with stable fraction of oxygen, resulting in decreased inspired partial pressure of oxygen and hypoxia. The normal physiologic response to hypoxia is increased ventilation, which can cause hypocapnia, suppressing respiratory drive and resulting in CSAs. The instability of the respiratory response results in cyclical CSAs followed by hyperventilation. This periodic breathing then causes arousals from sleep, driving further sleep fragmentation and exacerbation of baseline desaturation and instability in the cyclical respiratory response. There is individual variability in hypoxic chemoresponsiveness (loop gain). Compensatory mechanisms are most robust when an individual routinely dwells at high altitude, resulting in acclimatization, rather than traveling there for a brief stay. Genetics and cardiac output also contribute to the effectiveness of compensation to altitude.

CSA-HAPB is defined by the following ICSD-3 criteria: (1) Recent ascent to a high altitude (typically ≥ 2500 m, although some individuals may exhibit the disorder at altitudes as low as 1500 m); (2) the patient reports sleepiness, awakening with shortness of breath, snoring, witnessed apneas, or insomnia; (3) symptoms are clinically attributable to HAPB, or PSG, if performed, reveals recurrent CSAs or hypopneas primarily during non-REM sleep at a frequency of ≥ 5 events per hour; (4) the disorder is not better explained by another current sleep disorder, medical or neurological disorder, medication use (eg, narcotics), or SUD.⁸

Treatment options to improve nocturnal oxygen saturation and reduce or eliminate CSA-HAPB in nonacclimatized individuals include oxygen-enriched air, acetazolamide, or combination treatment with acetazolamide and automatic PAP (APAP).²² A meta-analysis looking at the effectiveness of acetazolamide in 8 different randomized controlled trials demonstrated that a dose of 250 mg per day was effective in improving sleep apnea at altitude as measured by a decrease in AHI, decrease in percentage of periodic breathing, and increasing oxygenation during sleep.¹⁵ The question of superiority of combined acetazolamide with APAP to placebo with APAP in treatment of high-altitude OSA was addressed in a randomized double-blind, placebo-controlled trial. The results showed that combined APAP (5-15 cm of water pressure) and acetazolamide (250 mg morning, 500 mg evening) decreased the AHI to normal range, whereas central events persisted in the APAP and placebo group.²³ In addition, Latshang and colleagues have demonstrated that ASV may not be as efficacious for controlling CSA-HAPB in nonacclimatized individuals compared with oxygen therapy and suggested that further research is warranted examining if ASV device algorithm adjustment improves efficacy of this therapeutic option.²⁴

Comorbidity-Induced CSA

Several medical conditions may be associated with CSA, including chronic kidney disease (CKD), pulmonary hypertension, acromegaly, and hypothyroidism. The common pathophysiologic link is that these disorders may result in alteration of ventilatory responses to CO₂, ultimately resulting in CSA.

As many as 10% of patients with CKD may experience CSA.^25,26 The complications encountered in CKD include fluid overload with pulmonary edema, chronic metabolic acidosis, and anemia. These can provoke hyperventilation in addition to poor sleep quality, triggering arousals that further drive CSA in these patients. Additional risk factors for CSA in this population include atrial fibrillation and cardiac dysfunction. Clinical interventions that have demonstrated reduction in CSA include hemodialysis at night vs daytime and using bicarbonate buffer vs acetate for hemodialysis ^22-24,26-29

Hypersecretion of growth hormone in acromegaly also results in hyperventilation contributing to CSA. While medical and surgical management of acromegaly results in a reduction in OSA, there is limited evidence on the outcome of the CSA after these interventions.

Hypothyroidism and CSA both present with similar symptoms of fatigue, daytime sleepiness, depression, and headaches. Studies suggest that respiratory muscle fatigue and decreased ventilatory response to hypercapnia and hypoxia contribute to apnea in this population. In one study, 27% of hypothyroid patients had a blunted response to hypercapnia, and 34% suffered from a blunted response to hypoxia. The same study showed universal reversal of the impairment following thyroid replacement therapy and return to euthyroid state.³⁰ Similarly, multiple studies have shown reversal of respiratory muscle fatigue after initiation of thyroid replacement.^30-32 Assessing thyroid function is an appropriate initial step during any sleep-disordered breathing workup, as it is a reversible cause of apnea. Up to 2.4% of patients presenting for PSG (and diagnosed with OSA) are found to have undiagnosed hypothyroidism.^32,33 In a military population, treatment of a secondary cause of CSA, such as hypothyroidism, could remove some administrative burden as well as improve service members’ quality of life.

If CSA persists despite previous treatment strategies, then clinicians should focus on the optimization of treatment for comorbid conditions. If that does not resolve CSA, CPAP should be used when AHI remains above 15 events per hour or ASV can be used.

Idiopathic CSA

There are limited data on the pathophysiology and prevalence of idiopathic CSA. In most cases it is hypocapnic CSA, which occurs after an arousal from sleep causing hyperventilation that causes hypocapnia below the apnea threshold similar to CSA-HAPB. Therapeutic options based on addressing underlying pathophysiology include increasing CO₂ by inhalation or addition of dead space. Additional therapeutic options to reduce the arousals and CSAs include hypnotics, such as zolpidem and acetazolamide, but these should be administered only with close clinical monitoring. If symptoms continue, CPAP or ASV may be trialed; however, limited clinical evidence of efficacy exists.¹⁵

For patients with moderate-to-severe CSA, an additional treatment option includes an implantable device (eg, Zoll remede¯), which stimulates the phrenic nerve to move the diaphragm and restore normal breathing. This device is not indicated for those with OSA. Based on data submitted to the US Food and Drug Administration, AHI is reduced by ≥ 50% in 51% of patients with the implanted device and by 11% in patients without the device. Five-year follow-up data show sustained improvements.³⁴

Hypercapnic CSA

CSA due to a medication or substance requires the following criteria: (1) the patient is taking an opioid or other respiratory depressant; (2) the patient reports sleepiness, awakening with shortness of breath, snoring, witnessed apneas, or insomnia (difficulty initiating or maintaining sleep, frequent awakenings, or nonrestorative sleep); (3) PSG reveals ≥ 5 CSAs and/or central hypopneas per hour of sleep; the number of CSAs and/or central hypopneas is > 50% of the total number of apneas and hypopneas; and there is no evidence of CSB; and (4) the disorder is not better explained by another current sleep disorder.⁸

Drugs that affect the respiratory centers, such as opiates and opioids, γ aminobutyric acid (GABA) type A and B receptor agonists, and P2Y(12) receptor antagonists such as ticagrelor, may result in alterations in ventilatory drive in the central nervous system respiratory centers, resulting in CSA.

Opioids are prescribed either for chronic pain or to treat opiate addiction with methadone, resulting in about one-third of chronic opioid users having some form of CSA.³⁵ CSA may be seen after opioids have been used for at least 2 months. A dose-dependent effect exists with high doses of opioids, typically resulting in hypoventilation, hypercapnia, and hypoxemia with ataxic or erratic breathing and a periodic breathing pattern similar to those described in CSA-HAPB or idiopathic CSA. About 14% to 60% of methadone patients also demonstrate CSA or ataxic breathing.^35,36

Benzodiazepines (GABA-A receptor agonists) and baclofen (a GABA-B receptor agonist) depress central ventilatory drive, blunt the response to hypoxia and hypercapnia, leading to CSAs, and increase risk for OSA by increasing upper airway obstruction through reduction in tone. Use of these medications with antidepressants or opioids further exacerbates this response.

Unlike the other medications previously described, ticagrelor, a first-line dual antiplatelet therapy medication indicated for acute coronary syndrome treatment, actually increases the activity of the respiratory centers but may result in CSA.

First-line treatment, if possible, is reduction in medication dose or complete withdrawal. Additional treatment options include PAP therapies: CPAP, BiPAP, ASV, and oxygen therapy with or without PAP.^37,38 The literature has demonstrated that for the treatment of opioid-associated CSA, ASV (in cases of normocapnia) and noninvasive ventilation (NIV)/BiPAP (in cases with hypercapnia or REM sleep hypoventilation) are superior treatment options when compared with conventional CPAP for elimination of respiratory events. CPAP with oxygen therapy and BiPAP with oxygen therapy are more effective than CPAP alone in reducing respiratory events. However, concerns remain that as with CSA in HF, CSA in chronic opioid users may serve as a physiologic protective mechanism to prevent further clinical injury from opioids. Similarly, as in the use of ASV in the SERVE-HF trial, focusing on elimination of respiratory events may prove detrimental. More studies are needed to determine whether reducing the number of CSA events in chronic opioid users is clinically beneficial when other health outcomes, such as cardiovascular, neurocognitive, hospital/intensive care unit admissions, and mortality risks are examined.

Neuromuscular-Induced CSA

CSA also is highly prevalent in neuromuscular conditions, such as amyotrophic lateral sclerosis, Duchenne muscular dystrophy, myotonic dystrophy, advanced multiple sclerosis, and acid maltase deficiency. There is reduced respiratory muscle strength and tone in these disorders, resulting in alveolar hypoventilation with hypercapnia. Given the hypercapnia, NIV/BiPAP is the first-line treatment to improve survival, gas exchange, symptom burden, and quality of life.

Stroke-Induced CSA

Extensive cerebrovascular events commonly precipitate sleep-related breathing disorders. The incidence increases in the acute phase of stroke and decreases 3 to 6 months poststroke; however, incidence also depends on the severity of the stroke.^7,39,40 Stroke also has been shown to be a predictor of CSA (odds ratio, 1.65; 95% CI, 1.50-1.82; P < .001) in a retrospective analysis of a large cohort of US veterans.² The location of the lesion often determines whether normocapnic or hypercapnic CSA will predominate, based on ventilatory instability resulting in normocapnia or reduced ventilatory drive resulting in hypercapnic CSA. PSG results and blood gases direct the treatment options. CSA with normocapnia is treated with ASV, and patients with hypercapnia/REM sleep hypoventilation are treated with NIV/BiPAP.

Conclusions

While much has been learned about CSA in recent decades, more evidence needs to be gathered to determine optimal treatment strategies and the impact on patient prognosis. The identification of CSA can lead to the diagnosis of previously unrecognized medical conditions. With proper diagnosis and treatment, we can optimize clinical management and improve patients’ prognosis and quality of life.

Acknowledgments

The authors thank the librarians of the Franzello Aeromedical Library in particular Sara Craycraft, Catherine Stahl, Kristen Young and Elizabeth Irvine for their support of this publication.

As the prevalence of obstructive sleep apnea (OSA) has steadily increased in the United States, so has the awareness of central sleep apnea (CSA). The hallmark of CSA is transient cessation of airflow during sleep due to a lack of respiratory effort triggered by the brain. This is in contrast to OSA, in which there is absence of airflow despite continued ventilatory effort due to physical airflow obstruction. The gold standard for the diagnosis and optimal treatment assessment of CSA is inlaboratory polysomnography (PSG) with esophageal manometry, but in practice, respiratory effort is generally estimated through oronasal flow and respiratory inductance plethysmography bands placed on the chest and abdomen during PSG.

Background

The literature has demonstrated a higher prevalence of moderate-to-severe OSA in the general population compared with that of CSA. While OSA is associated with worse clinical outcomes, more evidence is needed on the long-term clinical impact and optimal treatment strategies for CSA.¹ CSA is overrepresented among certain clinical populations. CSA is not frequently diagnosed in the active-duty population, but is increasing in the veteran population, especially in those with heart failure (HF), stroke, neuromuscular disorders, and opioid use. It is associated with increased admissions related to comorbid cardiovascular disorders and to an increased risk of death.^2-4 The clinical concerns with CSA parallel those of OSA. The absence of respiration (apneas and hypopneas due to lack of effort) results in sympathetic surge, compromise of oxygenation and ventilation, sleep fragmentation, and elevation in blood pressure. Symptoms such as excessive daytime sleepiness, morning headaches, witnessed apneas, and nocturnal arrhythmias are shared between the 2 disorders.

Ventilatory instability is the most widely accepted mechanism leading to CSA in patients. Loop gain is the concept used to explain ventilatory control. This feedback loop is influenced by controller gain (primarily represented by central and peripheral chemoreceptors causing changes in ventilation due to PaCO₂ [partial pressure of CO₂ in arterial blood] fluctuations), plant gain (includes lungs and respiratory muscles and their ability to eliminate CO₂), and circulation time (feedback between controller and plant).⁵

High loop gain and narrow CO₂ reserve contribute to ventilatory instability in CSA.⁶ Those with high loop gain have increased sensitivity to changes in CO₂. These patients tend to overbreathe in response to smaller increases in PaCO₂ compared with those with low loop gain. Once the PaCO₂ falls below an individual’s apneic threshold (AT), an apnea will occur.⁷ The brainstem then pauses ventilation to allow the PaCO₂ to rise back above the AT. CSAs also can occur in healthy individuals as they transition from wakefulness into non–rapid eye movement (REM) sleep in a phenomenon called sleep state oscillation, with a mechanism that is similar to hyperventilation-induced CSAs described earlier.

Primary CSA has been defined in the International Classification of Sleep Disorders 3rd edition (ICSD-3) with the following criteria: (1) diagnostic PSG with ≥ 5 events per hour of CSAs and/or central hypopneas per hour of sleep; the number of CSAs and/or central hypopneas is > 50% of the total number of apneas and hypopneas; and there is no evidence of Cheyne-Stokes breathing (CSB); (2) the patient reports sleepiness, awakening with shortness of breath, snoring, witnessed apneas, or insomnia; (3) there is no evidence of nocturnal hypoventilation; and (4) the disorder is not better explained by another medical use, substance use disorder (SUD), or other current sleep, medical, or neurologic disorder.⁸

A systematic clinical approach should be used to identify and treat CSA (Figure).^6,7

Nonhypercapnic CSA

Heart Failure–Induced CSA

The leading medical diagnosis causing CSA is congestive HF (CHF), and there is a correlation between HF severity and presence of CSA. In patients with stable CHF with HF reduced ejection fraction (HFrEF), CSA is highly prevalent, occurring in 25% to 40% of patients.⁹ In contrast to other subtypes of CSA where literature regarding prognosis is lacking, the literature is clear that patients with HFrEF with CSA have a worse prognosis, with increased risk of death independent of the severity of HF. This may be the result of CSA promoting malignant ventricular arrhythmias. The prevalence of CSA in HF with preserved ejection fraction (HFpEF) is about 18% to 30%.^10,11

A significant reduction in cardiac output results in circulatory delay between the lungs and chemoreceptors that produces CSB periodic breathing, which is characteristic of the most recognized form of CSA. Per the ICSD-3, CSA with CSB requires the following 4 findings: (1) PSG reveals ≥ 5 CSAs and/or central hypopneas per hour of sleep; there are at least 3 consecutive CSAs and/or central hypopneas separated by crescendo-decrescendo breathing with a cycle length of at least 40 seconds (ie, CSB pattern), and the number of CSAs and/or central hypopneas is > 50% of the total number of apneas and hypopneas; (2) the patient reports sleepiness, awakening with shortness of breath, snoring, witnessed apneas, or insomnia; (3) the breathing pattern is associated with atrial fibrillation/flutter, CHF, or a neurologic disorder; and (4) the disorder is not better explained by another current sleep disorder, medication use (eg, opioids), or SUD.⁸

Treatment of HF-induced CSA begins with guideline-based medical management with the goal of reducing pulmonary capillary wedge pressure or increasing left ventricular ejection fraction through means that may include cardiac resynchronization therapy or left ventricular assist devices, when clinically indicated. If medical optimization is not sufficient, the next step is continuous positive airway pressure (CPAP or PAP), followed by adaptive servo-ventilation (ASV) if the apnea-hypopnea index (AHI) remains > 15 events per hour and is clinically indicated.

ASV is a second-line PAP therapy modality that uses proprietary algorithms to provide variable amounts of pressure that alternate between expiratory and inspiratory phases of the respiratory cycle in combination with physician-set or automatic backup respiratory rate designed to stabilize ventilation in patients with CSA and CSB. The inability to adjust tidal volume, potentially resulting in insufficient tidal volumes or ventilation, results in the contraindication for its use in patients with CSA with comorbid conditions that may result in hypercapnic respiratory failure. These conditions include chronic hypoventilation in obesity hypoventilation syndrome (OHS), moderate-to-severe chronic obstructive pulmonary disease, chronic elevation of PaCO₂ on arterial blood gas > 45 mm Hg, and restrictive thoracic or neuromuscular disease.¹²

Although ASV is more effective in normalizing AHI in patients with HF and CSA than is CPAP therapy, the clinical indications for ASV in the setting of HFrEF changed drastically with the publication of the landmark SERVE-HF trial, which investigated the effects of adding ASV to guideline-based medical management on survival and cardiovascular outcomes in patients with HFrEF and predominant CSA.¹³ The study did not show a difference between the ASV and control groups for the primary endpoint: a composite of time to first event of death from any cause, lifesaving cardiovascular intervention (transplantation, implantation of a long-term ventricular assist device, resuscitation after sudden cardiac arrest, or appropriate lifesaving shock), or unplanned hospitalization for worsening HF. However, the study showed a statistically and clinically significant increased risk of all-cause and cardiovascular mortality in the ASV group compared with the control group.¹³ A possible explanation for the increased all-cause and cardiovascular mortality is that CSA potentially serves a protective mechanism that when eliminated results in deleterious clinical outcomes. This resulted in significant changes in the treatment algorithm for HF-induced CSA with left ventricular ejection fraction of at least 45% becoming the cutoff for therapeutic decisions.

Treatment-Emergent CSA

Treatment-emergent CSA (TECSA, also known as complex sleep apnea) has been defined by the ICSD-3 by the following criteria: (1) diagnostic PSG with ≥ 5 events per hour of predominantly obstructive events; (2) resolution of obstructive events with PAP without a backup rate and CSA index (CAI) ≥ 5 per hour with central events ≥ 50% of the AHI; and (3) CSA not better explained by another disorder.⁸ Patients with TECSA can be further classified into those who have transient events that resolve within weeks to months, those with persistent events, and those with delayed events that may develop weeks to months after initiating PAP therapy.¹⁴

PAP treatment can decrease the PaCO₂ below the AT due to removal of flow limitation in previously obstructed upper airways, resulting in TECSA.^15,16 PAP therapy has not been the only treatment where new CSA has been identified on initiation. A 2021 systematic review identified patients who developed new-onset CSA with mandibular advancement device (MAD), hypoglossal nerve stimulator, tongue protrusion device, and nasal expiratory PAP device use, as well as after tracheostomy, maxillofacial surgery, and other surgeries, such as nasal and uvulopalatopharyngoplasty.¹⁷

The prevalence of TECSA has been noted to range between 0.6% and 20.3%, but Nigam and colleagues estimated a prevalence of 8.4% in their systematic review.^11,14 The variability in prevalence between studies could be due to differences in study design (retrospective vs prospective vs cross-sectional), diagnostic and inclusion criteria, patient population, and type of study used (full-night vs split-night vs both).^18,19 Risk factors for TECSA include male sex; older age; lower body mass index; higher baseline AHI, CAI, and arousal index; chronic medical issues such as CHF and coronary artery disease; opioid use; higher CPAP settings; excessive mask leak; and bilevel PAP (BiPAP) use.²⁰ Identifying these risk factors is important, as patients with TECSA are at higher risk of discontinuing therapy and of developing PAP intolerance.^15,20

Most patients with TECSA can continue CPAP therapy with resolution of events over weeks to months, but treatment of comorbid conditions should be optimized as they could be contributing factors. Zeineddine and colleagues recommend continuation of CPAP for 3 months if the patient has minor or no symptoms.¹⁹ A 2018 systematic review noted that 14.3% to 46.2% of TECSA patients will have persistent TECSA and some will develop TECSA after at least 1 month of PAP therapy.¹⁴ For these patients and those with severe symptoms in spite of therapy, a switch to BiPAP spontaneous/timed (BiPAP-S/T) or ASV should be considered, if not contraindicated based on comorbidities.²¹ Medications such as acetazolamide, oxygen therapy, and CO₂ supplementation have also been discussed as alternative treatments, but these options should not be first-line therapies and should be used on a case-by-case basis as adjuncts to PAP therapy.^16,17

Altitude-Induced CSA

Also known as CSA due to high-altitude periodic breathing (CSA-HAPB), this form of CSA occurs in nearly all lowlanders at altitudes above 3000 m, with severity increasing with altitude.¹⁵ The exact altitude at which it occurs varies based on an individual’s physiology. CSA-HAPB occurs in response to the low barometric pressure at altitude, combined with stable fraction of oxygen, resulting in decreased inspired partial pressure of oxygen and hypoxia. The normal physiologic response to hypoxia is increased ventilation, which can cause hypocapnia, suppressing respiratory drive and resulting in CSAs. The instability of the respiratory response results in cyclical CSAs followed by hyperventilation. This periodic breathing then causes arousals from sleep, driving further sleep fragmentation and exacerbation of baseline desaturation and instability in the cyclical respiratory response. There is individual variability in hypoxic chemoresponsiveness (loop gain). Compensatory mechanisms are most robust when an individual routinely dwells at high altitude, resulting in acclimatization, rather than traveling there for a brief stay. Genetics and cardiac output also contribute to the effectiveness of compensation to altitude.

CSA-HAPB is defined by the following ICSD-3 criteria: (1) Recent ascent to a high altitude (typically ≥ 2500 m, although some individuals may exhibit the disorder at altitudes as low as 1500 m); (2) the patient reports sleepiness, awakening with shortness of breath, snoring, witnessed apneas, or insomnia; (3) symptoms are clinically attributable to HAPB, or PSG, if performed, reveals recurrent CSAs or hypopneas primarily during non-REM sleep at a frequency of ≥ 5 events per hour; (4) the disorder is not better explained by another current sleep disorder, medical or neurological disorder, medication use (eg, narcotics), or SUD.⁸

Treatment options to improve nocturnal oxygen saturation and reduce or eliminate CSA-HAPB in nonacclimatized individuals include oxygen-enriched air, acetazolamide, or combination treatment with acetazolamide and automatic PAP (APAP).²² A meta-analysis looking at the effectiveness of acetazolamide in 8 different randomized controlled trials demonstrated that a dose of 250 mg per day was effective in improving sleep apnea at altitude as measured by a decrease in AHI, decrease in percentage of periodic breathing, and increasing oxygenation during sleep.¹⁵ The question of superiority of combined acetazolamide with APAP to placebo with APAP in treatment of high-altitude OSA was addressed in a randomized double-blind, placebo-controlled trial. The results showed that combined APAP (5-15 cm of water pressure) and acetazolamide (250 mg morning, 500 mg evening) decreased the AHI to normal range, whereas central events persisted in the APAP and placebo group.²³ In addition, Latshang and colleagues have demonstrated that ASV may not be as efficacious for controlling CSA-HAPB in nonacclimatized individuals compared with oxygen therapy and suggested that further research is warranted examining if ASV device algorithm adjustment improves efficacy of this therapeutic option.²⁴

Comorbidity-Induced CSA

Several medical conditions may be associated with CSA, including chronic kidney disease (CKD), pulmonary hypertension, acromegaly, and hypothyroidism. The common pathophysiologic link is that these disorders may result in alteration of ventilatory responses to CO₂, ultimately resulting in CSA.

As many as 10% of patients with CKD may experience CSA.^25,26 The complications encountered in CKD include fluid overload with pulmonary edema, chronic metabolic acidosis, and anemia. These can provoke hyperventilation in addition to poor sleep quality, triggering arousals that further drive CSA in these patients. Additional risk factors for CSA in this population include atrial fibrillation and cardiac dysfunction. Clinical interventions that have demonstrated reduction in CSA include hemodialysis at night vs daytime and using bicarbonate buffer vs acetate for hemodialysis ^22-24,26-29

Hypersecretion of growth hormone in acromegaly also results in hyperventilation contributing to CSA. While medical and surgical management of acromegaly results in a reduction in OSA, there is limited evidence on the outcome of the CSA after these interventions.

Hypothyroidism and CSA both present with similar symptoms of fatigue, daytime sleepiness, depression, and headaches. Studies suggest that respiratory muscle fatigue and decreased ventilatory response to hypercapnia and hypoxia contribute to apnea in this population. In one study, 27% of hypothyroid patients had a blunted response to hypercapnia, and 34% suffered from a blunted response to hypoxia. The same study showed universal reversal of the impairment following thyroid replacement therapy and return to euthyroid state.³⁰ Similarly, multiple studies have shown reversal of respiratory muscle fatigue after initiation of thyroid replacement.^30-32 Assessing thyroid function is an appropriate initial step during any sleep-disordered breathing workup, as it is a reversible cause of apnea. Up to 2.4% of patients presenting for PSG (and diagnosed with OSA) are found to have undiagnosed hypothyroidism.^32,33 In a military population, treatment of a secondary cause of CSA, such as hypothyroidism, could remove some administrative burden as well as improve service members’ quality of life.

If CSA persists despite previous treatment strategies, then clinicians should focus on the optimization of treatment for comorbid conditions. If that does not resolve CSA, CPAP should be used when AHI remains above 15 events per hour or ASV can be used.

Idiopathic CSA

There are limited data on the pathophysiology and prevalence of idiopathic CSA. In most cases it is hypocapnic CSA, which occurs after an arousal from sleep causing hyperventilation that causes hypocapnia below the apnea threshold similar to CSA-HAPB. Therapeutic options based on addressing underlying pathophysiology include increasing CO₂ by inhalation or addition of dead space. Additional therapeutic options to reduce the arousals and CSAs include hypnotics, such as zolpidem and acetazolamide, but these should be administered only with close clinical monitoring. If symptoms continue, CPAP or ASV may be trialed; however, limited clinical evidence of efficacy exists.¹⁵

For patients with moderate-to-severe CSA, an additional treatment option includes an implantable device (eg, Zoll remede¯), which stimulates the phrenic nerve to move the diaphragm and restore normal breathing. This device is not indicated for those with OSA. Based on data submitted to the US Food and Drug Administration, AHI is reduced by ≥ 50% in 51% of patients with the implanted device and by 11% in patients without the device. Five-year follow-up data show sustained improvements.³⁴

Hypercapnic CSA

CSA due to a medication or substance requires the following criteria: (1) the patient is taking an opioid or other respiratory depressant; (2) the patient reports sleepiness, awakening with shortness of breath, snoring, witnessed apneas, or insomnia (difficulty initiating or maintaining sleep, frequent awakenings, or nonrestorative sleep); (3) PSG reveals ≥ 5 CSAs and/or central hypopneas per hour of sleep; the number of CSAs and/or central hypopneas is > 50% of the total number of apneas and hypopneas; and there is no evidence of CSB; and (4) the disorder is not better explained by another current sleep disorder.⁸

Drugs that affect the respiratory centers, such as opiates and opioids, γ aminobutyric acid (GABA) type A and B receptor agonists, and P2Y(12) receptor antagonists such as ticagrelor, may result in alterations in ventilatory drive in the central nervous system respiratory centers, resulting in CSA.

Opioids are prescribed either for chronic pain or to treat opiate addiction with methadone, resulting in about one-third of chronic opioid users having some form of CSA.³⁵ CSA may be seen after opioids have been used for at least 2 months. A dose-dependent effect exists with high doses of opioids, typically resulting in hypoventilation, hypercapnia, and hypoxemia with ataxic or erratic breathing and a periodic breathing pattern similar to those described in CSA-HAPB or idiopathic CSA. About 14% to 60% of methadone patients also demonstrate CSA or ataxic breathing.^35,36

Benzodiazepines (GABA-A receptor agonists) and baclofen (a GABA-B receptor agonist) depress central ventilatory drive, blunt the response to hypoxia and hypercapnia, leading to CSAs, and increase risk for OSA by increasing upper airway obstruction through reduction in tone. Use of these medications with antidepressants or opioids further exacerbates this response.

Unlike the other medications previously described, ticagrelor, a first-line dual antiplatelet therapy medication indicated for acute coronary syndrome treatment, actually increases the activity of the respiratory centers but may result in CSA.

First-line treatment, if possible, is reduction in medication dose or complete withdrawal. Additional treatment options include PAP therapies: CPAP, BiPAP, ASV, and oxygen therapy with or without PAP.^37,38 The literature has demonstrated that for the treatment of opioid-associated CSA, ASV (in cases of normocapnia) and noninvasive ventilation (NIV)/BiPAP (in cases with hypercapnia or REM sleep hypoventilation) are superior treatment options when compared with conventional CPAP for elimination of respiratory events. CPAP with oxygen therapy and BiPAP with oxygen therapy are more effective than CPAP alone in reducing respiratory events. However, concerns remain that as with CSA in HF, CSA in chronic opioid users may serve as a physiologic protective mechanism to prevent further clinical injury from opioids. Similarly, as in the use of ASV in the SERVE-HF trial, focusing on elimination of respiratory events may prove detrimental. More studies are needed to determine whether reducing the number of CSA events in chronic opioid users is clinically beneficial when other health outcomes, such as cardiovascular, neurocognitive, hospital/intensive care unit admissions, and mortality risks are examined.

Neuromuscular-Induced CSA

CSA also is highly prevalent in neuromuscular conditions, such as amyotrophic lateral sclerosis, Duchenne muscular dystrophy, myotonic dystrophy, advanced multiple sclerosis, and acid maltase deficiency. There is reduced respiratory muscle strength and tone in these disorders, resulting in alveolar hypoventilation with hypercapnia. Given the hypercapnia, NIV/BiPAP is the first-line treatment to improve survival, gas exchange, symptom burden, and quality of life.

Stroke-Induced CSA

Extensive cerebrovascular events commonly precipitate sleep-related breathing disorders. The incidence increases in the acute phase of stroke and decreases 3 to 6 months poststroke; however, incidence also depends on the severity of the stroke.^7,39,40 Stroke also has been shown to be a predictor of CSA (odds ratio, 1.65; 95% CI, 1.50-1.82; P < .001) in a retrospective analysis of a large cohort of US veterans.² The location of the lesion often determines whether normocapnic or hypercapnic CSA will predominate, based on ventilatory instability resulting in normocapnia or reduced ventilatory drive resulting in hypercapnic CSA. PSG results and blood gases direct the treatment options. CSA with normocapnia is treated with ASV, and patients with hypercapnia/REM sleep hypoventilation are treated with NIV/BiPAP.

Conclusions

While much has been learned about CSA in recent decades, more evidence needs to be gathered to determine optimal treatment strategies and the impact on patient prognosis. The identification of CSA can lead to the diagnosis of previously unrecognized medical conditions. With proper diagnosis and treatment, we can optimize clinical management and improve patients’ prognosis and quality of life.

Acknowledgments

The authors thank the librarians of the Franzello Aeromedical Library in particular Sara Craycraft, Catherine Stahl, Kristen Young and Elizabeth Irvine for their support of this publication.

Building the health care system of the future requires the thoughtful development and integration of innovative technologies to positively transform care.^1-4 Extended reality (XR) represents a spectrum of emerging technologies that have the potential to enhance health care. This includes virtual reality (VR), where a computer-generated visual experience fills the screen; augmented reality (AR), which allows users to see computer-generated images superimposed into an otherwise normal real-world field of view; and mixed reality (MR), which allows users to interact and manipulate computer-generated AR images.

Clinicians and researchers have begun exploring the potential of XR to address a wide variety of health care challenges. A recent systematic review concluded that many clinical studies in this area have small sample sizes and are in the preclinical, proof-of-concept stage, but demonstrate the potential and impact of the underlying VR, AR, and MR technologies.⁵ Common emerging health care uses for XR include medical education, training, presurgical planning, surgical guidance, distraction therapy for pain and anxiety, and home health indications, including rehabilitation.^5-39

Methods

The VA Palo Alto Health Care System (VAPAHCS) consists of 3 inpatient hospitals and 7 outpatient clinics, provides a full range of care services to > 90,000 enrolled veterans with 800 hospital beds, 3 nursing homes, and a 100-bed domiciliary. The facility also runs data-driven care projects in research, innovation, and evidence-based practice group under nursing services.⁴⁸ This project was performed by the VA National Center for Collaborative Healthcare Innovation at the VAPAHCS campus.

The combined technical system used for this assessment included a wireless communication network, AR/MR hardware, and software. Medivis AnatomyX software displayed an interactive human anatomy atlas segmented into about 6000 individual interactive parts. Medivis SurgicalAR received US Food and Drug Administration clearance for presurgical planning and was used to transform and display deidentified diagnostic images (eg, magnetic resonance images and computed tomography) in 3-dimensional (3D) interactive holograms (Figures 1 and 2).

 The wireless Microsoft HoloLens 2 AR/MR headset was used for viewing and sensor-enabled collaborative interaction. Multiple participants in the same physical location simultaneously participated and interacted with 3D holograms. The interactive hologram data were enabled for 3D stereoscopic viewing and manipulation.

Setting and Participants

We reviewed published studies that used questionnaires to evaluate institutions’ level of innovation and new technology user acceptance to develop the questionnaire.^49-56 Questions and methods were modified, with a focus on understanding the impact on hospital employees. The questionnaire consisted of 2 predemonstration and 3 postdemonstration sections. The first section included background questions. The second (predemonstration) and third (postdemonstration) sections provided matched questions on feelings about the VA. The fourth section included 2 unmatched questions about how the participant felt this technology would impact veterans and whether the VA should implement similar technologies. We used a 5-point Likert scale for sections 2, 3 and 4 (1 = not at all to 5 = extremely). Two unmatched free-text questions asked how the technology could be used in the participant’s hospital service, and another open-ended question asked for any additional comments. To reduce potential reporting bias, 2 VA employees that did not work at VAPAHCS assisted with the survey distribution and collection. VAPAHCS staff were informed by all employee email and facility intranet of the opportunity to participate; the voluntary demonstration and survey took place on February 10 and 11, 2020.

Data Analysis

All matching pre/post questions were analyzed together to determine statistically significant differences using the Wilcoxon signed rank matched pairs test and pooled t test. Survey respondents were also grouped by employment type to evaluate the impact on subgroups. Results were also grouped by VA tenure into 4 categorical 10-year increments (0-10, 11-20, 21-30, 31-40). Additionally, analysis of variance (ANOVA) was performed on employment types and VA tenure to understand whether there was a statistically significant difference in responses by these subgroups. Respondents’ optional free-text answers were manually reviewed by 2 authors (ZPV and DMA), classified, coded by the common themes, and analyzed for comparison.

Results

A total of 166 participants completed the predemonstration survey, which was a requirement for participating in the AR demonstration. Of those, 159 staff members (95.8%) also completed at least part of the postdemonstration paired structured questions, and their results were included in the analysis.

Paired Questions

For questions about how innovative the VA is, 108 of 152 participants (71.1%) provided higher scores after the demonstration, 42 (27.6%) had no change, and 2 (1.3%) provided decreased scores. The mean innovative score increased from 3.4 predemonstration to 4.5 postdemonstration on a Likert scale, which is a 1.1 point increase from predemonstration to postdemonstration (95% CI, 0.9- 1.2) or a 22% increase (95% CI, 18%-24%) (P < .001). Respondents level of excitement about VA also increased with 82 of 157 participants (52.2%) providing higher scores after the demonstration, 71 (45.2%) had no change, and 4 scores (2.5%) decreased. The predemonstration mean excitement score of 3.7 increased to 4.3 postdemonstration, which is a 0.6 point increase from before to after the demonstration (95% CI, 0.5-0.7) or a 12% increase (95% CI, 10%-14%) (P < .001). In the survey, 36 of 149 participants (24.2%) had higher scores for their expectation to continue working at VA postdemonstration, 109 (73.2%) had no change, and 4 scores (2.7%) decreased. The mean employee retention score increased from 4.2 predemonstration to 4.5 postdemonstration, which is a 0.3 point increase between pre/post (95% CI, 0.2-0.4) or a 6% increase (95% CI, 4%-8%) (P < .001)

The pre/post questions were analyzed using 1-way ANOVA by hospital department and VA tenure. The responses by department were not statistically significant. Of the 159 employees assessed, 101 respondents (63.5%) had 0 to 10 years VA tenure, 44 (27.7%) had 11 to 20 years, 10 (6.3%) had 21 to 30 years, and 4 (2.5%) had > 31 to 40 years. Length of VA tenure did not impact respondent excitement. Respondents opinions on innovation in the 0 to 10 year and the 11 to 20 year groups rose from 3.2 and 3.7 predemonstration to 4.3 and 4.6 postdemonstration, respectively (P < .001 for both statistical comparisons) (Table 2). Interestingly, the 0 to 10 group saw a 9% rise from a 4.0 score predemonstration to a 4.4 score postdemonstration (P < .001), indicating that the demonstration had a positive impact on their plans to continue employment at VA (Table 3).

Sex did not play a significant role in how respondents answered questions regarding VA excitement or innovation. However, there was a statistically significant difference in how male and female respondents answered the predemonstration question about their plans to continue VA employment, according to the Wilcoxon rank sum test. Predemonstration, female respondents had a mean score of 4.1, which was 6% lower than the 4.4 score of male colleagues (P = .04). Veteran status did have an impact on how respondents felt about VA innovation, and their plans to continue employment at VA. After the demonstration, veteran staff felt the VA was more innovative compared with nonveterans: 4.7 vs 4.4, respectively, a 6% difference (P = .02) Similarly, for the continued VA employment question, veterans had a mean score of 4.8 vs 4.4 for nonveterans, an 8% difference (P = .03) These results suggest that the demonstration had more of an impact on veteran employees vs nonveteran employees.

Unpaired Questions

There were 2 structured unpaired postdemonstration questions. Respondents agreed that similar technology would impact veteran health care with mean (SD) of 4.6 (0.6) and a median score of 5 on a 5-point Likert scale. Respondents also agreed on the importance of implementing similar innovations with mean (SD) of 4.7 (0.5), and a median score of 5.

The survey asked how this technology could benefit their hospital service department and had 64 responses. Forty-six respondents saw applications for education or patient care/surgery. Other responses shared excitement about the technology and its potential to positively impact patient education. There were 37 responses to the open-ended question: 21 respondents expressed excitement for the technology, and 10 respondents reiterated that the demonstration would be of benefit to patient care/surgery and training.

Discussion

Successful development, design, and deployment of any new health care tool depends on leveraging insights from the employees that will be using and supporting these systems. Correspondingly, understanding the impact that advanced technologies have on health care employees’ satisfaction, morale, and retention is critical to our overall institutional strategy. Our findings show that a one-time experience with AR/MR technology elicited positive employee reactions. Of note, the survey revealed statistically significant improvements in staff’s view of the VA, with the greatest positive impact for questions about innovation, followed by excitement to work at the VA, and likelihood to continue work at the VA. It is very disruptive and costly when health care employees leave, and improving employee satisfaction and morale is important for better patient care and patient satisfaction, which is priority for VAPAHCS leadership.^57-62

The paired predemonstration and postdemonstration scores were similarly high, nearing the top threshold available for the Likert scale (4.3 to 4.5). Furthermore, the least incremental improvement for these responses was observed for topics that had the highest initial baseline score. Therefore, the improvements observed for the paired questions may have more to do with the high baseline values.

Of additional interest, the self-reported likelihood of continuing to work at the VA increased the most for female employees, veteran employees, and employees with the least number of years at the VA. These demographic differences have important implications for VA staff recruitment and retention strategies.⁶² The unpaired questions about the impact on veteran care and whether the VA should continue similar work demonstrated extremely high support with median scores of 5 for both questions. The free-text postdemonstration responses also demonstrate similar positive themes, with a disposition for excitement about both the training and patient care applications for this technology. In addition, respondents felt strongly that this and other similar technologies will positively impact the health care for veterans and that the VA should continue these efforts.

Strengths and Limitations

A strength of this assessment is the ability to evaluate survey responses that were systematically collected and matched from the same individual immediately before and after exposure to the new technology. The free-text responses provided additional important information that both confirmed the results and provided additional valued supplementary guidance for future implementation strategies, which is critical for our translational implementation goals. An additional strength is that the voluntary surveys were managed by non-VAPAHCS colleagues, limiting potential bias. Importantly, the number of respondents allowed a statistically significant assessment of important health care employee metrics. These results have emphasized how being part of an innovative organization, and the introduction of advanced AR/MR technology, improve employees’ satisfaction and morale about where they work as well as their intention to stay at their institution.

A limitation of this assessment was the lack of comparative data for employee acceptance of other technologies at VAPAHCS. This limits our ability to differentiate whether the strong positive results observed in this evaluation were a result of the specific technology assessed, or of new and advanced health care technology in general. Nonetheless, our unpaired questions, which received extremely high scores, also included participant questions about comparing the system with other similar technologies. This assessment was also focused on veteran care, which limits generalizability.

Conclusions

One-time exposure to advanced AR technology for health care significantly increased employee morale as measured by excitement about working at the VA as well as employee intention to continue employment at the VA. These collateral benefits of the technology are particularly important in health care because our employees are our most important asset and improving employee morale equates to better patient care. Positive impacts were most pronounced for women employees, newer VA employees, and employees who are also veterans. These more detailed insights are also positioned to have a direct impact on employee recruitment and retention strategies. Additional valuable insights regarding the most applicable use of the technology in the clinical setting were also obtained. 

Acknowledgments

We thank Andrew Spiegelman, Hyewon Kim, Jonathan Sills, and Alexander Erickson for their assistance in developing the survey questions. We also thank Jason Rhodes and Mark Bulson for traveling to our facility to assist with managing the anonymous surveys during the demonstration event.