Medication to help prevent breast cancer is not recommended for women without increased risk, but could benefit women at increased risk for the disease, according to an update from the U.S. Preventive Services Task Force.

Dr. Cecil Fox/National Cancer Institute

SOURCEs: Owens DK et al. JAMA. 2019 Sept 3. doi: 10.1001/jama.2019.11885; Nelson HD et al. JAMA. 2019 Sept 3. doi: 10.1001/jama.2019.5780.

Medication to help prevent breast cancer is not recommended for women without increased risk, but could benefit women at increased risk for the disease, according to an update from the U.S. Preventive Services Task Force.

Dr. Cecil Fox/National Cancer Institute

SOURCEs: Owens DK et al. JAMA. 2019 Sept 3. doi: 10.1001/jama.2019.11885; Nelson HD et al. JAMA. 2019 Sept 3. doi: 10.1001/jama.2019.5780.

Medication to help prevent breast cancer is not recommended for women without increased risk, but could benefit women at increased risk for the disease, according to an update from the U.S. Preventive Services Task Force.

Dr. Cecil Fox/National Cancer Institute

SOURCEs: Owens DK et al. JAMA. 2019 Sept 3. doi: 10.1001/jama.2019.11885; Nelson HD et al. JAMA. 2019 Sept 3. doi: 10.1001/jama.2019.5780.

Almost a century after its discovery, insulin remains a life-saving yet costly medication: In the past 15 years, prices have risen more than 500%.¹ Patients may ask you why the insulin you prescribe is so expensive, and the complex process for determining drug costs makes it difficult to answer. But the bottom line is, patients need their insulin—and they want it without breaking the bank.

Thankfully, there are several strategies for reducing the cost of insulin. First and foremost, patients must be advised that not taking their prescribed insulin, or taking less insulin than prescribed, is not a safe alternative. An individualized cost-benefit analysis between patient and provider can help to determine the best option for each patient. After working in endocrinology for 5 years, I have learned the following 10 ways to help patients whose financial situations limit their access to insulin.

1 Try older insulins, including mixed insulin 70/30 or 50/50, insulin NPH, or regular insulin. Because the beneficial effects may not be as long lasting with these as with newer insulins on the market, your patient may need to test glucose levels more frequently. Also, insulin NPH and any mixed insulins are suspensions, not solutions, so patients will need to gently roll older insulins prior to use. Those in pen form may also have a shorter shelf life.

2 Switch to a syringe and vial. Although dosing can be less precise, this could be a viable option for patients with good vision and dexterity. This method helps patients save in 3 ways: (1) the insulin is less expensive; (2) syringes generally cost less (about $30 for 100) than pen needle tips (about $50 for 100); and (3) vials of NPH are longer-lasting suspensions that are stable for about 28 days once opened, compared to 14 days for pens.^2-4

3 Switch from a 30- to a 90-day supply of refills. This helps to lower copays. For example, a mail-order program (eg, Express Scripts) that ships from a warehouse typically offers lower pricing than a brick-and-mortar pharmacy with greater overhead. Many of these programs provide 2-pharmacist verification for accuracy and free home delivery of medications at a 10% discount, as well as 24-hour pharmacist access.⁵ The ease of obtaining prescriptions by this method also can help with medication adherence.

4 Patient assistance programs (PAPs) offered by insulin manufacturers can help lower costs for patients who find it difficult to afford their medication. Information on these programs is available on the respective company’s websites, usually in multiple languages (although some are limited to English and Spanish). Patients applying for a PAP must provide a proof of income and adhere to the program’s specific criteria. Renewal is typically required each year.^6-8

5 Copay cards are available to many patients with private insurance and may help make insulin more affordable. Patients may be able to receive a $25 monthly supply of insulin for up to 1 year (specific terms vary). Maximum contributions and contributions toward deductibles also vary by program, so patients need to familiarize themselves with what their particular copay card allows. Generally, copay cards are not a sustainable long-term solution; for one thing, they expire, and for another, emphasis should be placed on affordable medications rather than affording expensive medications.

[polldaddy:10400221]

Continue to: 6 External PAPs for patients on Medicare...

6 External PAPs for patients on Medicare can help lower the costs of prescription medications.⁹ A database of pharmaceutical PAPs is available on the Medicare website.¹⁰ Some PAPs may help patients on Medicare pay through the $5,100 coverage gap or “donut hole”—a term referring to a gap in prescription drug coverage once patients have met their prescription limit (all Medicare part D plans have a donut hole).^11,12 Patients and providers will need to read the fine print when applying for an external PAP, because some have a monthly or one-time start-up fee for processing the paperwork (and note, there is often paperwork for the relief program in addition to the PAP paperwork through the pharmaceutical company).

7 A Program of All-Inclusive Care for the Elderly (PACE) is available in many states; check medicare.gov to see if your state is eligible. For patients 55 and older on Medicare or Medicaid who do not opt for care at a nursing home facility, PACE may be able to provide care and coverage in the patient’s home or at a PACE facility. Services include primary care, hospital care, laboratory and x-ray services, medical specialty services, and prescription drugs. To be eligible for PACE services, the patient must live in the service area of a PACE organization and have a requirement for a nursing home-level of care (as certified by your state).

8 Shop around for the best deal. Encourage your patients to comparison shop for the best prices rather than accepting the first or only option at their usual pharmacy. Different pharmacies offer drugs at lower prices than competitors. Also, continually compare prices at GoodRx or HealthWarehouse.com. The latter—a fully licensed Internet-based pharmacy—sells FDA-approved medications at affordable prices in all 50 states, without the requirement for insurance coverage.

9 Use of a patch pump may be less expensive for patients with type 2 diabetes who are taking basal-bolus regimens. Patches slowly deliver single short-acting insulin (usually insulin aspart or lispro) that acts as a basal insulin, with an additional reservoir for prandial insulin at mealtime and for snacks. As there is a catheter in the patch, patients would not require the use of needles.¹³

10 Try removing mealtime insulin for patients with type 2 diabetes who need minimal mealtime insulin. Clinicians can initiate a safe trial of this removal by encouraging the patient to consume a low-carbohydrate diet, increase exercise, and/or use other noninsulin medications that are more affordable.

Continue to: The affordability of insulins...

The affordability of insulins is a potentially uncomfortable but necessary conversation to have with your patient. Providers are one of the best resources for patients who seek relief from financial difficulties. The recommendations discussed here can help providers and patients design a cost-conscious plan for insulin treatment. Although each recommendation is viable, the pros and cons must be weighed on a case-by-case basis. Providers and patients should also pay attention to the Senate Finance Committee’s ongoing discussions and possible resolutions that could result in lower insulin costs. Until legislation that lowers the prices of insulin comes to fruition, however, providers should continue to plan with their patients on how to best get their insulin at the lowest cost.

Test yourself with the poll here.

Almost a century after its discovery, insulin remains a life-saving yet costly medication: In the past 15 years, prices have risen more than 500%.¹ Patients may ask you why the insulin you prescribe is so expensive, and the complex process for determining drug costs makes it difficult to answer. But the bottom line is, patients need their insulin—and they want it without breaking the bank.

Thankfully, there are several strategies for reducing the cost of insulin. First and foremost, patients must be advised that not taking their prescribed insulin, or taking less insulin than prescribed, is not a safe alternative. An individualized cost-benefit analysis between patient and provider can help to determine the best option for each patient. After working in endocrinology for 5 years, I have learned the following 10 ways to help patients whose financial situations limit their access to insulin.

1 Try older insulins, including mixed insulin 70/30 or 50/50, insulin NPH, or regular insulin. Because the beneficial effects may not be as long lasting with these as with newer insulins on the market, your patient may need to test glucose levels more frequently. Also, insulin NPH and any mixed insulins are suspensions, not solutions, so patients will need to gently roll older insulins prior to use. Those in pen form may also have a shorter shelf life.

2 Switch to a syringe and vial. Although dosing can be less precise, this could be a viable option for patients with good vision and dexterity. This method helps patients save in 3 ways: (1) the insulin is less expensive; (2) syringes generally cost less (about $30 for 100) than pen needle tips (about $50 for 100); and (3) vials of NPH are longer-lasting suspensions that are stable for about 28 days once opened, compared to 14 days for pens.^2-4

3 Switch from a 30- to a 90-day supply of refills. This helps to lower copays. For example, a mail-order program (eg, Express Scripts) that ships from a warehouse typically offers lower pricing than a brick-and-mortar pharmacy with greater overhead. Many of these programs provide 2-pharmacist verification for accuracy and free home delivery of medications at a 10% discount, as well as 24-hour pharmacist access.⁵ The ease of obtaining prescriptions by this method also can help with medication adherence.

4 Patient assistance programs (PAPs) offered by insulin manufacturers can help lower costs for patients who find it difficult to afford their medication. Information on these programs is available on the respective company’s websites, usually in multiple languages (although some are limited to English and Spanish). Patients applying for a PAP must provide a proof of income and adhere to the program’s specific criteria. Renewal is typically required each year.^6-8

5 Copay cards are available to many patients with private insurance and may help make insulin more affordable. Patients may be able to receive a $25 monthly supply of insulin for up to 1 year (specific terms vary). Maximum contributions and contributions toward deductibles also vary by program, so patients need to familiarize themselves with what their particular copay card allows. Generally, copay cards are not a sustainable long-term solution; for one thing, they expire, and for another, emphasis should be placed on affordable medications rather than affording expensive medications.

[polldaddy:10400221]

Continue to: 6 External PAPs for patients on Medicare...

6 External PAPs for patients on Medicare can help lower the costs of prescription medications.⁹ A database of pharmaceutical PAPs is available on the Medicare website.¹⁰ Some PAPs may help patients on Medicare pay through the $5,100 coverage gap or “donut hole”—a term referring to a gap in prescription drug coverage once patients have met their prescription limit (all Medicare part D plans have a donut hole).^11,12 Patients and providers will need to read the fine print when applying for an external PAP, because some have a monthly or one-time start-up fee for processing the paperwork (and note, there is often paperwork for the relief program in addition to the PAP paperwork through the pharmaceutical company).

7 A Program of All-Inclusive Care for the Elderly (PACE) is available in many states; check medicare.gov to see if your state is eligible. For patients 55 and older on Medicare or Medicaid who do not opt for care at a nursing home facility, PACE may be able to provide care and coverage in the patient’s home or at a PACE facility. Services include primary care, hospital care, laboratory and x-ray services, medical specialty services, and prescription drugs. To be eligible for PACE services, the patient must live in the service area of a PACE organization and have a requirement for a nursing home-level of care (as certified by your state).

8 Shop around for the best deal. Encourage your patients to comparison shop for the best prices rather than accepting the first or only option at their usual pharmacy. Different pharmacies offer drugs at lower prices than competitors. Also, continually compare prices at GoodRx or HealthWarehouse.com. The latter—a fully licensed Internet-based pharmacy—sells FDA-approved medications at affordable prices in all 50 states, without the requirement for insurance coverage.

9 Use of a patch pump may be less expensive for patients with type 2 diabetes who are taking basal-bolus regimens. Patches slowly deliver single short-acting insulin (usually insulin aspart or lispro) that acts as a basal insulin, with an additional reservoir for prandial insulin at mealtime and for snacks. As there is a catheter in the patch, patients would not require the use of needles.¹³

10 Try removing mealtime insulin for patients with type 2 diabetes who need minimal mealtime insulin. Clinicians can initiate a safe trial of this removal by encouraging the patient to consume a low-carbohydrate diet, increase exercise, and/or use other noninsulin medications that are more affordable.

Continue to: The affordability of insulins...

The affordability of insulins is a potentially uncomfortable but necessary conversation to have with your patient. Providers are one of the best resources for patients who seek relief from financial difficulties. The recommendations discussed here can help providers and patients design a cost-conscious plan for insulin treatment. Although each recommendation is viable, the pros and cons must be weighed on a case-by-case basis. Providers and patients should also pay attention to the Senate Finance Committee’s ongoing discussions and possible resolutions that could result in lower insulin costs. Until legislation that lowers the prices of insulin comes to fruition, however, providers should continue to plan with their patients on how to best get their insulin at the lowest cost.

Test yourself with the poll here.

Almost a century after its discovery, insulin remains a life-saving yet costly medication: In the past 15 years, prices have risen more than 500%.¹ Patients may ask you why the insulin you prescribe is so expensive, and the complex process for determining drug costs makes it difficult to answer. But the bottom line is, patients need their insulin—and they want it without breaking the bank.

Thankfully, there are several strategies for reducing the cost of insulin. First and foremost, patients must be advised that not taking their prescribed insulin, or taking less insulin than prescribed, is not a safe alternative. An individualized cost-benefit analysis between patient and provider can help to determine the best option for each patient. After working in endocrinology for 5 years, I have learned the following 10 ways to help patients whose financial situations limit their access to insulin.

1 Try older insulins, including mixed insulin 70/30 or 50/50, insulin NPH, or regular insulin. Because the beneficial effects may not be as long lasting with these as with newer insulins on the market, your patient may need to test glucose levels more frequently. Also, insulin NPH and any mixed insulins are suspensions, not solutions, so patients will need to gently roll older insulins prior to use. Those in pen form may also have a shorter shelf life.

2 Switch to a syringe and vial. Although dosing can be less precise, this could be a viable option for patients with good vision and dexterity. This method helps patients save in 3 ways: (1) the insulin is less expensive; (2) syringes generally cost less (about $30 for 100) than pen needle tips (about $50 for 100); and (3) vials of NPH are longer-lasting suspensions that are stable for about 28 days once opened, compared to 14 days for pens.^2-4

3 Switch from a 30- to a 90-day supply of refills. This helps to lower copays. For example, a mail-order program (eg, Express Scripts) that ships from a warehouse typically offers lower pricing than a brick-and-mortar pharmacy with greater overhead. Many of these programs provide 2-pharmacist verification for accuracy and free home delivery of medications at a 10% discount, as well as 24-hour pharmacist access.⁵ The ease of obtaining prescriptions by this method also can help with medication adherence.

4 Patient assistance programs (PAPs) offered by insulin manufacturers can help lower costs for patients who find it difficult to afford their medication. Information on these programs is available on the respective company’s websites, usually in multiple languages (although some are limited to English and Spanish). Patients applying for a PAP must provide a proof of income and adhere to the program’s specific criteria. Renewal is typically required each year.^6-8

5 Copay cards are available to many patients with private insurance and may help make insulin more affordable. Patients may be able to receive a $25 monthly supply of insulin for up to 1 year (specific terms vary). Maximum contributions and contributions toward deductibles also vary by program, so patients need to familiarize themselves with what their particular copay card allows. Generally, copay cards are not a sustainable long-term solution; for one thing, they expire, and for another, emphasis should be placed on affordable medications rather than affording expensive medications.

[polldaddy:10400221]

Continue to: 6 External PAPs for patients on Medicare...

6 External PAPs for patients on Medicare can help lower the costs of prescription medications.⁹ A database of pharmaceutical PAPs is available on the Medicare website.¹⁰ Some PAPs may help patients on Medicare pay through the $5,100 coverage gap or “donut hole”—a term referring to a gap in prescription drug coverage once patients have met their prescription limit (all Medicare part D plans have a donut hole).^11,12 Patients and providers will need to read the fine print when applying for an external PAP, because some have a monthly or one-time start-up fee for processing the paperwork (and note, there is often paperwork for the relief program in addition to the PAP paperwork through the pharmaceutical company).

7 A Program of All-Inclusive Care for the Elderly (PACE) is available in many states; check medicare.gov to see if your state is eligible. For patients 55 and older on Medicare or Medicaid who do not opt for care at a nursing home facility, PACE may be able to provide care and coverage in the patient’s home or at a PACE facility. Services include primary care, hospital care, laboratory and x-ray services, medical specialty services, and prescription drugs. To be eligible for PACE services, the patient must live in the service area of a PACE organization and have a requirement for a nursing home-level of care (as certified by your state).

8 Shop around for the best deal. Encourage your patients to comparison shop for the best prices rather than accepting the first or only option at their usual pharmacy. Different pharmacies offer drugs at lower prices than competitors. Also, continually compare prices at GoodRx or HealthWarehouse.com. The latter—a fully licensed Internet-based pharmacy—sells FDA-approved medications at affordable prices in all 50 states, without the requirement for insurance coverage.

9 Use of a patch pump may be less expensive for patients with type 2 diabetes who are taking basal-bolus regimens. Patches slowly deliver single short-acting insulin (usually insulin aspart or lispro) that acts as a basal insulin, with an additional reservoir for prandial insulin at mealtime and for snacks. As there is a catheter in the patch, patients would not require the use of needles.¹³

10 Try removing mealtime insulin for patients with type 2 diabetes who need minimal mealtime insulin. Clinicians can initiate a safe trial of this removal by encouraging the patient to consume a low-carbohydrate diet, increase exercise, and/or use other noninsulin medications that are more affordable.

Continue to: The affordability of insulins...

The affordability of insulins is a potentially uncomfortable but necessary conversation to have with your patient. Providers are one of the best resources for patients who seek relief from financial difficulties. The recommendations discussed here can help providers and patients design a cost-conscious plan for insulin treatment. Although each recommendation is viable, the pros and cons must be weighed on a case-by-case basis. Providers and patients should also pay attention to the Senate Finance Committee’s ongoing discussions and possible resolutions that could result in lower insulin costs. Until legislation that lowers the prices of insulin comes to fruition, however, providers should continue to plan with their patients on how to best get their insulin at the lowest cost.

Test yourself with the poll here.

Genotype-guided selection of oral P2Y ₁₂ inhibitors for patients having percutaneous coronary intervention with stent implantation derives no clinical benefits overall when compared to standard treatment, according to results of the large, randomized POPular Genetics trial, although genotype guidance did result in lower rates of primary minor bleeding.

The study was presented at the annual congress of the European Society of Cardiology Study in Paris and published simultaneously in the New England Journal of Medicine.

CDC/Janice Carr

POPular Genetics (CYP2C19 Genotype-Guided Antiplatelet Therapy in ST-Segment Elevation Myocardial Infarction Patients – Patient Outcome After Primary PCI) randomized 2,488 patients who had PCI to either P2Y₁₂ inhibitor on the basis of early genetic testing for the CYP2C19 gene (1,242 patients) or standard treatment with either ticagrelor or prasugrel (1,246 patients) for 12 months. In the genotype-guided group, patients were assigned to one of two arms depending on results; carriers of CYP2C19*2 or CYP2C19*3 loss-of-function alleles received ticagrelor or prasugrel, and non-carriers receive clopidogrel. The study was conducted from Jun. 2011 to Apr. 2018.

Net adverse clinical events, which included any-cause death, myocardial infarction, stent thrombosis, stroke or major bleeding based on the Platelet Inhibition and Patient Outcomes (PLATO) criteria at 12 months were similar between both groups: 5.1% in the genotype-guided patients and 5.9% in the standard-treatment group (P less than .001), but rates of PLATO major or minor bleeding were 9.8% and 12.5%, respectively (P = .04).

When secondary outcomes were evaluated, no significant differences emerged between the two groups. Secondary outcomes included combined thrombotic outcomes (death from vascular causes, myocardial infarction, stent thrombosis or stroke; 2.7% for the genotype-guided group vs. 3.3% in the standard-treatment group), and PLATO major bleeding (2.3% in both groups). The difference in the primary bleeding outcomes between the groups was driven by a lower incidence of PLATO minor bleeding in the genotype-guided group, 7.6% vs. 10.5%.

The two takeaways from POPular Genetics, said Daniel M.F. Claassens, MD, and coauthors, are that giving clopidogrel to patients without a CYP2C19 loss-of-function allele did not elevate their risk of combined any-cause death and other adverse cardiac outcomes, including major bleeding, 12 months after PCI; and that giving clopidogrel to the genotype-guided group lowered the risk of minor bleeding.

Dr. Claassens and coauthors noted that since the Netherlands trial was designed in 2011, the development of newer-generation stents has considerably lowered rates of thrombotic events after acute coronary syndromes. “With the lower-than-anticipated incidence of the primary combined outcome in our trial, the prespecified noninferiority margin was wider relative to the incidence than originally expected,” they said. While the primary combined outcome was 21% higher than the incidence in the standard-treatment group at the upper end of the 95% confidence interval, the incidence was 11% higher in the standard-treatment group at the observed upper end of the 95% CI. This “gives stronger support to the conclusion that genotype-guided P2Y₁₂ treatment is noninferior to standard treatment for the occurrence of thrombotic events,” Dr. Claassens and coauthors said.

The study report noted a number of limitations, including that more polymorphisms of the CyP2C19 gene may be linked to increased thrombotic or bleeding risk. “Therefore, our strategy based solely on the CYP2C19 genotype may not be the most useful strategy for some patients,” Dr. Claassens and coauthors said.

POPular Genetics received funding from the Netherlands Organization for Health Research and Development (ZonMw). Dr. Claassens receives grants from ZonMw and non-financial support from Spartan Biosciences.

SOURCE: Claassens DMF, et al. N Engl J. Med. Published online September 3, doi.org/10.1016/S0140-6736(19)31996-8.

Genotype-guided selection of oral P2Y ₁₂ inhibitors for patients having percutaneous coronary intervention with stent implantation derives no clinical benefits overall when compared to standard treatment, according to results of the large, randomized POPular Genetics trial, although genotype guidance did result in lower rates of primary minor bleeding.

The study was presented at the annual congress of the European Society of Cardiology Study in Paris and published simultaneously in the New England Journal of Medicine.

CDC/Janice Carr

POPular Genetics (CYP2C19 Genotype-Guided Antiplatelet Therapy in ST-Segment Elevation Myocardial Infarction Patients – Patient Outcome After Primary PCI) randomized 2,488 patients who had PCI to either P2Y₁₂ inhibitor on the basis of early genetic testing for the CYP2C19 gene (1,242 patients) or standard treatment with either ticagrelor or prasugrel (1,246 patients) for 12 months. In the genotype-guided group, patients were assigned to one of two arms depending on results; carriers of CYP2C19*2 or CYP2C19*3 loss-of-function alleles received ticagrelor or prasugrel, and non-carriers receive clopidogrel. The study was conducted from Jun. 2011 to Apr. 2018.

Net adverse clinical events, which included any-cause death, myocardial infarction, stent thrombosis, stroke or major bleeding based on the Platelet Inhibition and Patient Outcomes (PLATO) criteria at 12 months were similar between both groups: 5.1% in the genotype-guided patients and 5.9% in the standard-treatment group (P less than .001), but rates of PLATO major or minor bleeding were 9.8% and 12.5%, respectively (P = .04).

When secondary outcomes were evaluated, no significant differences emerged between the two groups. Secondary outcomes included combined thrombotic outcomes (death from vascular causes, myocardial infarction, stent thrombosis or stroke; 2.7% for the genotype-guided group vs. 3.3% in the standard-treatment group), and PLATO major bleeding (2.3% in both groups). The difference in the primary bleeding outcomes between the groups was driven by a lower incidence of PLATO minor bleeding in the genotype-guided group, 7.6% vs. 10.5%.

The two takeaways from POPular Genetics, said Daniel M.F. Claassens, MD, and coauthors, are that giving clopidogrel to patients without a CYP2C19 loss-of-function allele did not elevate their risk of combined any-cause death and other adverse cardiac outcomes, including major bleeding, 12 months after PCI; and that giving clopidogrel to the genotype-guided group lowered the risk of minor bleeding.

Dr. Claassens and coauthors noted that since the Netherlands trial was designed in 2011, the development of newer-generation stents has considerably lowered rates of thrombotic events after acute coronary syndromes. “With the lower-than-anticipated incidence of the primary combined outcome in our trial, the prespecified noninferiority margin was wider relative to the incidence than originally expected,” they said. While the primary combined outcome was 21% higher than the incidence in the standard-treatment group at the upper end of the 95% confidence interval, the incidence was 11% higher in the standard-treatment group at the observed upper end of the 95% CI. This “gives stronger support to the conclusion that genotype-guided P2Y₁₂ treatment is noninferior to standard treatment for the occurrence of thrombotic events,” Dr. Claassens and coauthors said.

The study report noted a number of limitations, including that more polymorphisms of the CyP2C19 gene may be linked to increased thrombotic or bleeding risk. “Therefore, our strategy based solely on the CYP2C19 genotype may not be the most useful strategy for some patients,” Dr. Claassens and coauthors said.

POPular Genetics received funding from the Netherlands Organization for Health Research and Development (ZonMw). Dr. Claassens receives grants from ZonMw and non-financial support from Spartan Biosciences.

SOURCE: Claassens DMF, et al. N Engl J. Med. Published online September 3, doi.org/10.1016/S0140-6736(19)31996-8.

Genotype-guided selection of oral P2Y ₁₂ inhibitors for patients having percutaneous coronary intervention with stent implantation derives no clinical benefits overall when compared to standard treatment, according to results of the large, randomized POPular Genetics trial, although genotype guidance did result in lower rates of primary minor bleeding.

The study was presented at the annual congress of the European Society of Cardiology Study in Paris and published simultaneously in the New England Journal of Medicine.

CDC/Janice Carr

POPular Genetics (CYP2C19 Genotype-Guided Antiplatelet Therapy in ST-Segment Elevation Myocardial Infarction Patients – Patient Outcome After Primary PCI) randomized 2,488 patients who had PCI to either P2Y₁₂ inhibitor on the basis of early genetic testing for the CYP2C19 gene (1,242 patients) or standard treatment with either ticagrelor or prasugrel (1,246 patients) for 12 months. In the genotype-guided group, patients were assigned to one of two arms depending on results; carriers of CYP2C19*2 or CYP2C19*3 loss-of-function alleles received ticagrelor or prasugrel, and non-carriers receive clopidogrel. The study was conducted from Jun. 2011 to Apr. 2018.

Net adverse clinical events, which included any-cause death, myocardial infarction, stent thrombosis, stroke or major bleeding based on the Platelet Inhibition and Patient Outcomes (PLATO) criteria at 12 months were similar between both groups: 5.1% in the genotype-guided patients and 5.9% in the standard-treatment group (P less than .001), but rates of PLATO major or minor bleeding were 9.8% and 12.5%, respectively (P = .04).

When secondary outcomes were evaluated, no significant differences emerged between the two groups. Secondary outcomes included combined thrombotic outcomes (death from vascular causes, myocardial infarction, stent thrombosis or stroke; 2.7% for the genotype-guided group vs. 3.3% in the standard-treatment group), and PLATO major bleeding (2.3% in both groups). The difference in the primary bleeding outcomes between the groups was driven by a lower incidence of PLATO minor bleeding in the genotype-guided group, 7.6% vs. 10.5%.

The two takeaways from POPular Genetics, said Daniel M.F. Claassens, MD, and coauthors, are that giving clopidogrel to patients without a CYP2C19 loss-of-function allele did not elevate their risk of combined any-cause death and other adverse cardiac outcomes, including major bleeding, 12 months after PCI; and that giving clopidogrel to the genotype-guided group lowered the risk of minor bleeding.

Dr. Claassens and coauthors noted that since the Netherlands trial was designed in 2011, the development of newer-generation stents has considerably lowered rates of thrombotic events after acute coronary syndromes. “With the lower-than-anticipated incidence of the primary combined outcome in our trial, the prespecified noninferiority margin was wider relative to the incidence than originally expected,” they said. While the primary combined outcome was 21% higher than the incidence in the standard-treatment group at the upper end of the 95% confidence interval, the incidence was 11% higher in the standard-treatment group at the observed upper end of the 95% CI. This “gives stronger support to the conclusion that genotype-guided P2Y₁₂ treatment is noninferior to standard treatment for the occurrence of thrombotic events,” Dr. Claassens and coauthors said.

The study report noted a number of limitations, including that more polymorphisms of the CyP2C19 gene may be linked to increased thrombotic or bleeding risk. “Therefore, our strategy based solely on the CYP2C19 genotype may not be the most useful strategy for some patients,” Dr. Claassens and coauthors said.

POPular Genetics received funding from the Netherlands Organization for Health Research and Development (ZonMw). Dr. Claassens receives grants from ZonMw and non-financial support from Spartan Biosciences.

SOURCE: Claassens DMF, et al. N Engl J. Med. Published online September 3, doi.org/10.1016/S0140-6736(19)31996-8.

A number of medications commonly prescribed by rheumatologists may interact with cannabidiol oil, investigators at the Imperial College Healthcare NHS Trust, London, reported.

“Patients are increasingly requesting information concerning the safety of CBD oil,” Taryn Youngstein, MD, and associates said in letter to the editor in Rheumatology, but current guidelines on the use of medical cannabis do “not address the potential interactions between CBD oil and medicines frequently used in the rheumatology clinic.”

The most important potential CBD interaction, they suggested, may be with corticosteroids. Hydrocortisone and prednisolone both inhibit the cytochrome P450 enzyme CYP3A, but CBD is a potent inhibitor of CYP3A, so “concomitant use may decrease glucocorticoid clearance and increase risk of systemic [corticosteroid] side effects,” the investigators wrote.

CBD also is known to inhibit the cytochrome P450 isozymes CYP2C9, CYP2D6, CYP2C19, CYP3A4, and CYP1A2, which, alone or in combination, are involved in the metabolization of naproxen, tramadol, amitriptyline, and tofacitinib (Xeljanz), according to a literature search done via the college’s medicine information department that also used the British National Formulary and the Natural Medicines online interaction checker.

The Janus kinase inhibitor tofacitinib is included among the possible interactions, but the other Food and Drug Administration–approved JAK inhibitor, baricitinib (Olumiant), is primarily metabolized by the kidneys and should not have significant interaction with CBD, Dr. Youngstein and associates said. Most of the conventional synthetic and biologic disease-modifying antirheumatic drugs, including methotrexate, hydroxychloroquine, adalimumab (Humira), and abatacept (Orencia), also are expected to be relatively free from CBD interactions.

This first published report on interactions between CBD oil and common rheumatology medications “highlights the importance of taking comprehensive drug histories, by asking directly about drugs considered alternative medicines and food supplements,” they said.

The investigators declared no conflicts of interest, and there was no specific funding for the study.

rfranki@mdedge.com

SOURCE: Wilson-Morkeh H et al. Rheumatology. 2019 July 29. doi: 10.1093/rheumatology/kez304.

A number of medications commonly prescribed by rheumatologists may interact with cannabidiol oil, investigators at the Imperial College Healthcare NHS Trust, London, reported.

“Patients are increasingly requesting information concerning the safety of CBD oil,” Taryn Youngstein, MD, and associates said in letter to the editor in Rheumatology, but current guidelines on the use of medical cannabis do “not address the potential interactions between CBD oil and medicines frequently used in the rheumatology clinic.”

The most important potential CBD interaction, they suggested, may be with corticosteroids. Hydrocortisone and prednisolone both inhibit the cytochrome P450 enzyme CYP3A, but CBD is a potent inhibitor of CYP3A, so “concomitant use may decrease glucocorticoid clearance and increase risk of systemic [corticosteroid] side effects,” the investigators wrote.

CBD also is known to inhibit the cytochrome P450 isozymes CYP2C9, CYP2D6, CYP2C19, CYP3A4, and CYP1A2, which, alone or in combination, are involved in the metabolization of naproxen, tramadol, amitriptyline, and tofacitinib (Xeljanz), according to a literature search done via the college’s medicine information department that also used the British National Formulary and the Natural Medicines online interaction checker.

The Janus kinase inhibitor tofacitinib is included among the possible interactions, but the other Food and Drug Administration–approved JAK inhibitor, baricitinib (Olumiant), is primarily metabolized by the kidneys and should not have significant interaction with CBD, Dr. Youngstein and associates said. Most of the conventional synthetic and biologic disease-modifying antirheumatic drugs, including methotrexate, hydroxychloroquine, adalimumab (Humira), and abatacept (Orencia), also are expected to be relatively free from CBD interactions.

This first published report on interactions between CBD oil and common rheumatology medications “highlights the importance of taking comprehensive drug histories, by asking directly about drugs considered alternative medicines and food supplements,” they said.

The investigators declared no conflicts of interest, and there was no specific funding for the study.

rfranki@mdedge.com

SOURCE: Wilson-Morkeh H et al. Rheumatology. 2019 July 29. doi: 10.1093/rheumatology/kez304.

A number of medications commonly prescribed by rheumatologists may interact with cannabidiol oil, investigators at the Imperial College Healthcare NHS Trust, London, reported.

“Patients are increasingly requesting information concerning the safety of CBD oil,” Taryn Youngstein, MD, and associates said in letter to the editor in Rheumatology, but current guidelines on the use of medical cannabis do “not address the potential interactions between CBD oil and medicines frequently used in the rheumatology clinic.”

The most important potential CBD interaction, they suggested, may be with corticosteroids. Hydrocortisone and prednisolone both inhibit the cytochrome P450 enzyme CYP3A, but CBD is a potent inhibitor of CYP3A, so “concomitant use may decrease glucocorticoid clearance and increase risk of systemic [corticosteroid] side effects,” the investigators wrote.

CBD also is known to inhibit the cytochrome P450 isozymes CYP2C9, CYP2D6, CYP2C19, CYP3A4, and CYP1A2, which, alone or in combination, are involved in the metabolization of naproxen, tramadol, amitriptyline, and tofacitinib (Xeljanz), according to a literature search done via the college’s medicine information department that also used the British National Formulary and the Natural Medicines online interaction checker.

The Janus kinase inhibitor tofacitinib is included among the possible interactions, but the other Food and Drug Administration–approved JAK inhibitor, baricitinib (Olumiant), is primarily metabolized by the kidneys and should not have significant interaction with CBD, Dr. Youngstein and associates said. Most of the conventional synthetic and biologic disease-modifying antirheumatic drugs, including methotrexate, hydroxychloroquine, adalimumab (Humira), and abatacept (Orencia), also are expected to be relatively free from CBD interactions.

This first published report on interactions between CBD oil and common rheumatology medications “highlights the importance of taking comprehensive drug histories, by asking directly about drugs considered alternative medicines and food supplements,” they said.

The investigators declared no conflicts of interest, and there was no specific funding for the study.

rfranki@mdedge.com

SOURCE: Wilson-Morkeh H et al. Rheumatology. 2019 July 29. doi: 10.1093/rheumatology/kez304.

For too many of us, a good night’s sleep is a rare occurrence. Lack of quality sleep has profound negative effects on our health, safety, and wellbeing. An estimated 50 to 70 million Americans have sleep disturbances, including 10% to 17% of men and 3% to 9% of women with moderate to severe obstructive sleep apnea (OSA).¹ Not only is OSA highly prevalent, 82% to 93% of individuals with moderate to severe OSA are unaware they have it, and it remains undiagnosed.²

OSA is a potentially serious medical disorder affecting the heart, brain, and metabolism. These physiological changes negatively impact public safety, occupational and academic achievement, and even mortality.

This Cleveland Clinic Journal of Medicine supplement presents a state-of-the-art review of OSA, including the health and societal consequences of OSA and current treatment options. The goal of this publication is to inform and educate healthcare providers from all backgrounds and levels of care who are interested in improving patient outcomes through attention to sleep medicine.

Because OSA is prevalent and underdiagnosed, Jessica Vensel Rundo, MD, MS, reviews the symptoms of OSA, clinical presentation, and the readily available, effective screening tools for detecting sleep apnea. Greater awareness and screening for sleep disturbances informs the need for further diagnostic tests such as laboratory polysomnography and home sleep apnea testing.

The link between OSA and the heart is presented by Reena Mehra, MD, MS, with an overview of the physiology of sleep-heart interactions and the association of OSA and cardiovascular health. Dr. Mehra also reviews central sleep apnea and discusses 2 newer therapies for it: adaptive servoventilation and phrenic nerve stimulation.

Beyond heart health, OSA also adversely affects quality of life, safety, and other important health factors. Harneet Walia, MD, discusses consequences of sleep apnea such as daytime sleepiness, fatigue, drowsy driving, depression, metabolic diseases, and cognitive impairment.

Several treatment options exist for patients diagnosed with OSA. Positive airway pressure (PAP) therapy is the gold standard for treatment of OSA. Colleen G. Lance, MD, reviews and presents case scenarios about the efficacy of PAP therapy, features of continuous PAP therapy, and innovative strategies to improve adherence to therapy.

In addition to PAP therapy, there are alternative treatments for OSA that may benefit some patients.  Tina Waters, MD, considers alternatives to PAP therapy, such as lifestyle changes, expiratory PAP therapy, oral appliances, upper airway surgery, and hypoglossal nerve stimulation.

I hope you enjoy this supplement and find it useful to improving the health and quality-of-life outcomes of patients in your care.

For too many of us, a good night’s sleep is a rare occurrence. Lack of quality sleep has profound negative effects on our health, safety, and wellbeing. An estimated 50 to 70 million Americans have sleep disturbances, including 10% to 17% of men and 3% to 9% of women with moderate to severe obstructive sleep apnea (OSA).¹ Not only is OSA highly prevalent, 82% to 93% of individuals with moderate to severe OSA are unaware they have it, and it remains undiagnosed.²

OSA is a potentially serious medical disorder affecting the heart, brain, and metabolism. These physiological changes negatively impact public safety, occupational and academic achievement, and even mortality.

This Cleveland Clinic Journal of Medicine supplement presents a state-of-the-art review of OSA, including the health and societal consequences of OSA and current treatment options. The goal of this publication is to inform and educate healthcare providers from all backgrounds and levels of care who are interested in improving patient outcomes through attention to sleep medicine.

Because OSA is prevalent and underdiagnosed, Jessica Vensel Rundo, MD, MS, reviews the symptoms of OSA, clinical presentation, and the readily available, effective screening tools for detecting sleep apnea. Greater awareness and screening for sleep disturbances informs the need for further diagnostic tests such as laboratory polysomnography and home sleep apnea testing.

The link between OSA and the heart is presented by Reena Mehra, MD, MS, with an overview of the physiology of sleep-heart interactions and the association of OSA and cardiovascular health. Dr. Mehra also reviews central sleep apnea and discusses 2 newer therapies for it: adaptive servoventilation and phrenic nerve stimulation.

Beyond heart health, OSA also adversely affects quality of life, safety, and other important health factors. Harneet Walia, MD, discusses consequences of sleep apnea such as daytime sleepiness, fatigue, drowsy driving, depression, metabolic diseases, and cognitive impairment.

Several treatment options exist for patients diagnosed with OSA. Positive airway pressure (PAP) therapy is the gold standard for treatment of OSA. Colleen G. Lance, MD, reviews and presents case scenarios about the efficacy of PAP therapy, features of continuous PAP therapy, and innovative strategies to improve adherence to therapy.

In addition to PAP therapy, there are alternative treatments for OSA that may benefit some patients.  Tina Waters, MD, considers alternatives to PAP therapy, such as lifestyle changes, expiratory PAP therapy, oral appliances, upper airway surgery, and hypoglossal nerve stimulation.

I hope you enjoy this supplement and find it useful to improving the health and quality-of-life outcomes of patients in your care.

For too many of us, a good night’s sleep is a rare occurrence. Lack of quality sleep has profound negative effects on our health, safety, and wellbeing. An estimated 50 to 70 million Americans have sleep disturbances, including 10% to 17% of men and 3% to 9% of women with moderate to severe obstructive sleep apnea (OSA).¹ Not only is OSA highly prevalent, 82% to 93% of individuals with moderate to severe OSA are unaware they have it, and it remains undiagnosed.²

OSA is a potentially serious medical disorder affecting the heart, brain, and metabolism. These physiological changes negatively impact public safety, occupational and academic achievement, and even mortality.

This Cleveland Clinic Journal of Medicine supplement presents a state-of-the-art review of OSA, including the health and societal consequences of OSA and current treatment options. The goal of this publication is to inform and educate healthcare providers from all backgrounds and levels of care who are interested in improving patient outcomes through attention to sleep medicine.

Because OSA is prevalent and underdiagnosed, Jessica Vensel Rundo, MD, MS, reviews the symptoms of OSA, clinical presentation, and the readily available, effective screening tools for detecting sleep apnea. Greater awareness and screening for sleep disturbances informs the need for further diagnostic tests such as laboratory polysomnography and home sleep apnea testing.

The link between OSA and the heart is presented by Reena Mehra, MD, MS, with an overview of the physiology of sleep-heart interactions and the association of OSA and cardiovascular health. Dr. Mehra also reviews central sleep apnea and discusses 2 newer therapies for it: adaptive servoventilation and phrenic nerve stimulation.

Beyond heart health, OSA also adversely affects quality of life, safety, and other important health factors. Harneet Walia, MD, discusses consequences of sleep apnea such as daytime sleepiness, fatigue, drowsy driving, depression, metabolic diseases, and cognitive impairment.

Several treatment options exist for patients diagnosed with OSA. Positive airway pressure (PAP) therapy is the gold standard for treatment of OSA. Colleen G. Lance, MD, reviews and presents case scenarios about the efficacy of PAP therapy, features of continuous PAP therapy, and innovative strategies to improve adherence to therapy.

In addition to PAP therapy, there are alternative treatments for OSA that may benefit some patients.  Tina Waters, MD, considers alternatives to PAP therapy, such as lifestyle changes, expiratory PAP therapy, oral appliances, upper airway surgery, and hypoglossal nerve stimulation.

I hope you enjoy this supplement and find it useful to improving the health and quality-of-life outcomes of patients in your care.

Multiple sclerosis (MS) is one of the leading causes of disability and many efforts have been implemented to help expediate diagnosis and initiate early, effective treatment. With rapidly changing guidelines and treatment indications, it can be difficult discerning when to start a disease-modifying therapy in the early spectrum of MS, such as clinically and radiologically isolated syndrome; how to discuss MS management in women of childbearing age; or how to use the new guidelines to confirm an MS diagnosis. 

Click here to read the supplement and earn 1 AMA Category 1 Credit ^TM by learning about these topics.

Click here to read the supplement. 

Multiple sclerosis (MS) is one of the leading causes of disability and many efforts have been implemented to help expediate diagnosis and initiate early, effective treatment. With rapidly changing guidelines and treatment indications, it can be difficult discerning when to start a disease-modifying therapy in the early spectrum of MS, such as clinically and radiologically isolated syndrome; how to discuss MS management in women of childbearing age; or how to use the new guidelines to confirm an MS diagnosis. 

Click here to read the supplement and earn 1 AMA Category 1 Credit ^TM by learning about these topics.

Click here to read the supplement. 

Multiple sclerosis (MS) is one of the leading causes of disability and many efforts have been implemented to help expediate diagnosis and initiate early, effective treatment. With rapidly changing guidelines and treatment indications, it can be difficult discerning when to start a disease-modifying therapy in the early spectrum of MS, such as clinically and radiologically isolated syndrome; how to discuss MS management in women of childbearing age; or how to use the new guidelines to confirm an MS diagnosis. 

Click here to read the supplement and earn 1 AMA Category 1 Credit ^TM by learning about these topics.

Click here to read the supplement. 

DEFINITION

Obstructive sleep apnea (OSA) occurs when there are recurrent episodes of upper airway collapse and obstruction during sleep associated with arousals with or without oxygen desaturations. The oropharynx in the back of the throat collapses during OSA events to cause arousal or oxygen desaturation or both resulting in fragmented sleep.

PREVALENCE

Studies reveal OSA is prevalent. A 2015 study in Switzerland reported 50% of men and 23% of women had at least moderate OSA.¹ In 2002, the Sleep Heart Health study found that 24% of men and 9% of women have at least mild OSA.² In the Wisconsin Sleep Study Cohort, it was reported that 10% of men and 3% of women age 30 to 49 have at least moderate OSA, while 17% of men and 9% of women age 50 to 70 have at least moderate OSA.³ OSA is highly underrecognized and it is estimated that 82% of men and 93% of women in the United States with OSA are undiagnosed.⁴

SYMPTOMS

RISK FACTORS

The risk of OSA is influenced by unmodifiable and modifiable factors. Unmodifiable risk factors include male sex, age, and race. Genetic predisposition or a family history of OSA as well as cranial facial anatomy resulting in narrow airways may impart higher risk of OSA. Modifiable risk factors include obesity, medications that cause muscle relaxation and narrowing of the airway (opiates, benzodiazepines, alcohol), endocrine disorders (hypothyroidism, polycystic ovarian syndrome), smoking, and nasal congestion or obstruction.⁶

Sex

Men are at higher risk for OSA than women although once women reach menopause they have a risk similar to men. Postmenopausal women on hormone replacement therapy were found to have lower rates of OSA, suggesting that loss of hormones results in greater risk of OSA.^7,8 Women also have more OSA during rapid eye movement (REM) sleep and less OSA when sleeping supine, whereas most men have OSA when sleeping supine.^9,10 OSA is less severe in women compared with men of similar body mass index (BMI).¹¹ Symptoms vary in men and women: snoring and witnessed apneas are more common in men whereas insomnia and excessive daytime sleepiness are more common in women.¹¹ This may account for delayed diagnosis and the higher mortality in women compared with men.

Age

The risk of OSA increases with age. In a study of men 65 or older, the prevalence of moderate OSA was 23% in men younger than 72 and 30% in men older than 80.¹² By comparison, the prevalence of moderate OSA in men 30 to 40 years was 10%.³ Increased risk of OSA with age may be due to age-related reduction in slow wave sleep (ie, deep sleep), which is protective against sleep-disordered breathing and airway collapse.¹³ Older adults are also less symptomatic, reporting less daytime sleepiness and fatigue.¹⁴

Race

The Sleep Heart Health Study found a slightly increased risk of moderate to severe OSA in blacks (20%) and American Indians (23%) compared with whites (17%).² Another study showed the  prevalence of OSA was 30% in whites, 32% in blacks, 38% in Hispanics, and 39% in Chinese individuals.¹⁵ A higher prevalence of OSA in young blacks (≤ 25 years) compared with whites was reported,¹⁶ although another study found no differences based on race in older patients.¹⁷ These differences among racial groups may be due to variations in craniofacial anatomy.

Obesity

There is a correlation between increased risk of OSA and obesity (BMI > 30 kg/m²) and its correlates of greater waist-to-hip ratio and neck circumference.² A 10% increase in body weight results in a sixfold increase in moderate to severe OSA and increases the apnea–hypopnea index (AHI; number of breath pauses or respiratory events per hour) by 32% whereas a 10% decrease in weight decreases the AHI by 26%.¹⁸

COMORBIDITIES

OSA is associated with a number of comorbid conditions including stroke, myocardial infarction, hypertension, hyperlipidemia, glucose intolerance, diabetes, arrhythmias including atrial fibrillation, pulmonary hypertension, congestive heart failure, and depression. Patients with moderate or severe OSA are at higher risk of these comorbid conditions.¹⁹

Patients with cardiovascular disease have a very high prevalence of OSA: hypertension (83% mild to 30% moderate to severe OSA), heart failure (55% to 12%), arrhythmias (50% to 20%), stroke (75% to 57%), and coronary heart disease (65% to 38%).²⁰ Increased awareness and early diagnosis of OSA is critical to reducing cardiovascular disease burden.

Sleep history

A sleep history starts with determining the patient’s total sleep time, based on time to bed, time to fall asleep, and time of wake up, including any difficulty falling asleep, staying asleep, or daytime naps.

Symptoms. Daytime naps generally indicate a sleep deficit or sleep that is not refreshing. A review of sleep and daytime symptoms associated with OSA (Table 1) helps determine if excessive daytime sleepiness or unrefreshing sleep is out of proportion with the amount of sleep the patient is getting at night.

Some patients with OSA may have memory or concentration issues or feel like they have attention deficit disorder. In fact some patients are diagnosed with attention deficit disorder because of their insufficient sleep or unrefreshing sleep.

Drowsy driving is a special concern in patients with untreated OSA and sleep deprivation. Many patients have drowsy driving episodes or difficulty staying awake during long-distance driving. Caffeine use is also important information as excessive caffeine may be used to combat sleepiness during the day.

The Epworth Sleepiness Scale is a clinical screening tool that presents 8 situations for patients to consider and indicate their level of sleepiness and likelihood of falling asleep (never = 0; slight = 1; moderate = 2, high = 3).^21,22 A total score ≥ 10 is considered abnormal in that the patient is excessively sleepy compared with most people.

Risk factors and comorbid conditions. OSA risk factors and comorbidities, including a BMI obesity assessment, should be reviewed with patients. Nasal congestion or mouth breathing especially at night could be due to airway obstruction increasing the risk of OSA. Family history of OSA, tobacco, alcohol use, other medical conditions, and medications should also be discussed.

Physical examination

• Neck circumference greater than 17 inches for men or greater than 16 inches for women
• BMI greater than 30
• Friedman class tongue position class 3 or greater (Figure 1)
• Mouth features (present/enlarged tonsils, macroglossia, jaw misalignment)
• Nasal abnormalities (turbinate hypertrophy, deviated septum).⁵

Patients with Friedman palate positions class 3 and 4 have a higher risk of OSA due to airway crowding during sleep when the airway naturally collapses a little and is even more restricted.

Narrow airways or oropharyngeal crowding can also be due to a swollen, enlarged, or elongated uvula; present or enlarged tonsils; or lateral wall narrowing. Alone or in combination, these features can contribute to airway obstruction.

Other signs in the mouth suggestive of obstruction are macroglossia (enlarged tongue) and tongue ridging. Tongue ridging or scalloping impressions typically occur during sleep and are caused by the tongue moving forward to open the airway and pressing against the teeth.

Retrognathia (lower jaw offset behind upper jaw) can narrow the airway and increase the risk of OSA as can a high arch palate, overbite (upper teeth forward), or overjet (upper teeth over the top of lower teeth).

A nasal examination for nasal valve collapse (ie, nostril collapses with inhalation), deviated septum, and inferior turbinate hypertrophy impart an increased risk of OSA.

Screening tools

In addition to the Epworth Sleepiness Scale, the STOP-BANG questionnaire can help determine if a patient should be tested further for OSA. The STOP-BANG questionnaire consists of 8 yes-no questions where more than 2 yes responses indicate the patient is at higher risk for moderate to severe OSA (93% sensitivity): Snore, Tired, Observed stopped breathing, high blood Pressure, BMI > 35 kg/m², Age > 50, Neck > 15.75 inches, Gender = male).²³

Polysomnography

Home sleep apnea test

HSATs record 4 to 7 parameters including airflow (thermal and nasal pressure), effort (inductive ple­thysmography), and oximetry. No electroencephalogram is used, so sleep is not recorded; it is assumed the patient is sleeping for the duration of the test. As such, respiratory events are based on oxygen desaturations and reduced airflow and pressure as well as chest and abdomen effort. The raw data are edited and manually scored and reviewed by a sleep specialist.²⁵

Although the HSAT is convenient for many patients, it underestimates the severity of sleep-related breathing disorders. HSAT is intended to confirm OSA in patients with a high likelihood of OSA based on their sleep history.²⁶ It is ideally employed for adult patients with no major medical problems or other sleep problems who are at high risk for moderate to severe OSA based on the STOP-BANG questionnaire or those with daytime sleepiness and 2 of the 3 symptoms of snoring, witnessed apnea, or hypertension.²⁷

A negative or inconclusive HSAT warrants a PSG to ensure the patient does not have OSA. Use of HSAT is contraindicated in patients with

• Significant cardiopulmonary disease
• Potential weakness due to a neuro­muscular condition
• Awake hypoventilation or high risk for sleep-related hypoventilation (severe obesity)
• History of stroke
• Chronic opioid use
• Severe insomnia
• Symptoms of other significant sleep disorders
• Environmental/personal factors that would preclude adequate acquisition and interpretation of data (disruptions from children, pets, other factors).²⁷

DIAGNOSTIC CRITERIA

Respiratory events captured on a PSG or HSAT

The OSA diagnostic criteria are based on the occurrence of obstructive respiratory events recorded during sleep such as apneas, hypopneas, and respiratory event-related arousals.

Hypopneas. A hypopnea is a respiratory event resulting in reduced airflow. The America Association of Sleep Medicine’s preferred definition is a reduction in nasal pressure of at least 30% for 10 seconds or longer with 3% or greater oxygen desaturation or an electroencephalogram arousal. Another acceptable definition is at least 30% reduction in thoracoabdominal movement or airflow with 4% or greater oxygen desaturation, which is used by the Centers for Medicare and Medicaid Services and other insurers.^29,30 Hypopnea requires greater oxygen desaturation and is not dependent on arousals, which can sometimes make it more challenging to identify OSA (Figure 2).

Respiratory event-related arousals. Respiratory event-related arousals are respiratory events not meeting apnea or hypopnea criteria. They are measured as a sequence of breaths of 10 or more seconds with increasing respiratory effort or flattening of the nasal pressure waveform leading to arousal (Figure 2).²⁹ Respiratory event-related arousals are disruptive to sleep and have many of the same consequences as apneas and hypopneas.

Severity

SUMMARY

OSA results from airway collapse and obstruction during sleep, often causing arousal from sleep with or without oxygen desaturation. The prevalence of OSA is underestimated and it is underdiagnosed despite known risk factors and comorbid conditions. Screening for OSA with a sleep history, simple upper airway examination, and quick validated screening tool like the STOP-BANG or Epworth Sleepiness Scale aid in identifying the need for testing for OSA. A laboratory sleep study with a PSG can confirm the diagnosis and severity of OSA. HSATs are available to confirm the diagnosis of OSA in patients at high risk for moderate to severe OSA.

DEFINITION

Obstructive sleep apnea (OSA) occurs when there are recurrent episodes of upper airway collapse and obstruction during sleep associated with arousals with or without oxygen desaturations. The oropharynx in the back of the throat collapses during OSA events to cause arousal or oxygen desaturation or both resulting in fragmented sleep.

PREVALENCE

Studies reveal OSA is prevalent. A 2015 study in Switzerland reported 50% of men and 23% of women had at least moderate OSA.¹ In 2002, the Sleep Heart Health study found that 24% of men and 9% of women have at least mild OSA.² In the Wisconsin Sleep Study Cohort, it was reported that 10% of men and 3% of women age 30 to 49 have at least moderate OSA, while 17% of men and 9% of women age 50 to 70 have at least moderate OSA.³ OSA is highly underrecognized and it is estimated that 82% of men and 93% of women in the United States with OSA are undiagnosed.⁴

SYMPTOMS

RISK FACTORS

The risk of OSA is influenced by unmodifiable and modifiable factors. Unmodifiable risk factors include male sex, age, and race. Genetic predisposition or a family history of OSA as well as cranial facial anatomy resulting in narrow airways may impart higher risk of OSA. Modifiable risk factors include obesity, medications that cause muscle relaxation and narrowing of the airway (opiates, benzodiazepines, alcohol), endocrine disorders (hypothyroidism, polycystic ovarian syndrome), smoking, and nasal congestion or obstruction.⁶

Sex

Men are at higher risk for OSA than women although once women reach menopause they have a risk similar to men. Postmenopausal women on hormone replacement therapy were found to have lower rates of OSA, suggesting that loss of hormones results in greater risk of OSA.^7,8 Women also have more OSA during rapid eye movement (REM) sleep and less OSA when sleeping supine, whereas most men have OSA when sleeping supine.^9,10 OSA is less severe in women compared with men of similar body mass index (BMI).¹¹ Symptoms vary in men and women: snoring and witnessed apneas are more common in men whereas insomnia and excessive daytime sleepiness are more common in women.¹¹ This may account for delayed diagnosis and the higher mortality in women compared with men.

Age

The risk of OSA increases with age. In a study of men 65 or older, the prevalence of moderate OSA was 23% in men younger than 72 and 30% in men older than 80.¹² By comparison, the prevalence of moderate OSA in men 30 to 40 years was 10%.³ Increased risk of OSA with age may be due to age-related reduction in slow wave sleep (ie, deep sleep), which is protective against sleep-disordered breathing and airway collapse.¹³ Older adults are also less symptomatic, reporting less daytime sleepiness and fatigue.¹⁴

Race

The Sleep Heart Health Study found a slightly increased risk of moderate to severe OSA in blacks (20%) and American Indians (23%) compared with whites (17%).² Another study showed the  prevalence of OSA was 30% in whites, 32% in blacks, 38% in Hispanics, and 39% in Chinese individuals.¹⁵ A higher prevalence of OSA in young blacks (≤ 25 years) compared with whites was reported,¹⁶ although another study found no differences based on race in older patients.¹⁷ These differences among racial groups may be due to variations in craniofacial anatomy.

Obesity

There is a correlation between increased risk of OSA and obesity (BMI > 30 kg/m²) and its correlates of greater waist-to-hip ratio and neck circumference.² A 10% increase in body weight results in a sixfold increase in moderate to severe OSA and increases the apnea–hypopnea index (AHI; number of breath pauses or respiratory events per hour) by 32% whereas a 10% decrease in weight decreases the AHI by 26%.¹⁸

COMORBIDITIES

OSA is associated with a number of comorbid conditions including stroke, myocardial infarction, hypertension, hyperlipidemia, glucose intolerance, diabetes, arrhythmias including atrial fibrillation, pulmonary hypertension, congestive heart failure, and depression. Patients with moderate or severe OSA are at higher risk of these comorbid conditions.¹⁹

Patients with cardiovascular disease have a very high prevalence of OSA: hypertension (83% mild to 30% moderate to severe OSA), heart failure (55% to 12%), arrhythmias (50% to 20%), stroke (75% to 57%), and coronary heart disease (65% to 38%).²⁰ Increased awareness and early diagnosis of OSA is critical to reducing cardiovascular disease burden.

Sleep history

A sleep history starts with determining the patient’s total sleep time, based on time to bed, time to fall asleep, and time of wake up, including any difficulty falling asleep, staying asleep, or daytime naps.

Symptoms. Daytime naps generally indicate a sleep deficit or sleep that is not refreshing. A review of sleep and daytime symptoms associated with OSA (Table 1) helps determine if excessive daytime sleepiness or unrefreshing sleep is out of proportion with the amount of sleep the patient is getting at night.

Some patients with OSA may have memory or concentration issues or feel like they have attention deficit disorder. In fact some patients are diagnosed with attention deficit disorder because of their insufficient sleep or unrefreshing sleep.

Drowsy driving is a special concern in patients with untreated OSA and sleep deprivation. Many patients have drowsy driving episodes or difficulty staying awake during long-distance driving. Caffeine use is also important information as excessive caffeine may be used to combat sleepiness during the day.

The Epworth Sleepiness Scale is a clinical screening tool that presents 8 situations for patients to consider and indicate their level of sleepiness and likelihood of falling asleep (never = 0; slight = 1; moderate = 2, high = 3).^21,22 A total score ≥ 10 is considered abnormal in that the patient is excessively sleepy compared with most people.

Risk factors and comorbid conditions. OSA risk factors and comorbidities, including a BMI obesity assessment, should be reviewed with patients. Nasal congestion or mouth breathing especially at night could be due to airway obstruction increasing the risk of OSA. Family history of OSA, tobacco, alcohol use, other medical conditions, and medications should also be discussed.

Physical examination

• Neck circumference greater than 17 inches for men or greater than 16 inches for women
• BMI greater than 30
• Friedman class tongue position class 3 or greater (Figure 1)
• Mouth features (present/enlarged tonsils, macroglossia, jaw misalignment)
• Nasal abnormalities (turbinate hypertrophy, deviated septum).⁵

Patients with Friedman palate positions class 3 and 4 have a higher risk of OSA due to airway crowding during sleep when the airway naturally collapses a little and is even more restricted.

Narrow airways or oropharyngeal crowding can also be due to a swollen, enlarged, or elongated uvula; present or enlarged tonsils; or lateral wall narrowing. Alone or in combination, these features can contribute to airway obstruction.

Other signs in the mouth suggestive of obstruction are macroglossia (enlarged tongue) and tongue ridging. Tongue ridging or scalloping impressions typically occur during sleep and are caused by the tongue moving forward to open the airway and pressing against the teeth.

Retrognathia (lower jaw offset behind upper jaw) can narrow the airway and increase the risk of OSA as can a high arch palate, overbite (upper teeth forward), or overjet (upper teeth over the top of lower teeth).

A nasal examination for nasal valve collapse (ie, nostril collapses with inhalation), deviated septum, and inferior turbinate hypertrophy impart an increased risk of OSA.

Screening tools

In addition to the Epworth Sleepiness Scale, the STOP-BANG questionnaire can help determine if a patient should be tested further for OSA. The STOP-BANG questionnaire consists of 8 yes-no questions where more than 2 yes responses indicate the patient is at higher risk for moderate to severe OSA (93% sensitivity): Snore, Tired, Observed stopped breathing, high blood Pressure, BMI > 35 kg/m², Age > 50, Neck > 15.75 inches, Gender = male).²³

Polysomnography

Home sleep apnea test

HSATs record 4 to 7 parameters including airflow (thermal and nasal pressure), effort (inductive ple­thysmography), and oximetry. No electroencephalogram is used, so sleep is not recorded; it is assumed the patient is sleeping for the duration of the test. As such, respiratory events are based on oxygen desaturations and reduced airflow and pressure as well as chest and abdomen effort. The raw data are edited and manually scored and reviewed by a sleep specialist.²⁵

Although the HSAT is convenient for many patients, it underestimates the severity of sleep-related breathing disorders. HSAT is intended to confirm OSA in patients with a high likelihood of OSA based on their sleep history.²⁶ It is ideally employed for adult patients with no major medical problems or other sleep problems who are at high risk for moderate to severe OSA based on the STOP-BANG questionnaire or those with daytime sleepiness and 2 of the 3 symptoms of snoring, witnessed apnea, or hypertension.²⁷

A negative or inconclusive HSAT warrants a PSG to ensure the patient does not have OSA. Use of HSAT is contraindicated in patients with

• Significant cardiopulmonary disease
• Potential weakness due to a neuro­muscular condition
• Awake hypoventilation or high risk for sleep-related hypoventilation (severe obesity)
• History of stroke
• Chronic opioid use
• Severe insomnia
• Symptoms of other significant sleep disorders
• Environmental/personal factors that would preclude adequate acquisition and interpretation of data (disruptions from children, pets, other factors).²⁷

DIAGNOSTIC CRITERIA

Respiratory events captured on a PSG or HSAT

The OSA diagnostic criteria are based on the occurrence of obstructive respiratory events recorded during sleep such as apneas, hypopneas, and respiratory event-related arousals.

Hypopneas. A hypopnea is a respiratory event resulting in reduced airflow. The America Association of Sleep Medicine’s preferred definition is a reduction in nasal pressure of at least 30% for 10 seconds or longer with 3% or greater oxygen desaturation or an electroencephalogram arousal. Another acceptable definition is at least 30% reduction in thoracoabdominal movement or airflow with 4% or greater oxygen desaturation, which is used by the Centers for Medicare and Medicaid Services and other insurers.^29,30 Hypopnea requires greater oxygen desaturation and is not dependent on arousals, which can sometimes make it more challenging to identify OSA (Figure 2).

Respiratory event-related arousals. Respiratory event-related arousals are respiratory events not meeting apnea or hypopnea criteria. They are measured as a sequence of breaths of 10 or more seconds with increasing respiratory effort or flattening of the nasal pressure waveform leading to arousal (Figure 2).²⁹ Respiratory event-related arousals are disruptive to sleep and have many of the same consequences as apneas and hypopneas.

Severity

SUMMARY

OSA results from airway collapse and obstruction during sleep, often causing arousal from sleep with or without oxygen desaturation. The prevalence of OSA is underestimated and it is underdiagnosed despite known risk factors and comorbid conditions. Screening for OSA with a sleep history, simple upper airway examination, and quick validated screening tool like the STOP-BANG or Epworth Sleepiness Scale aid in identifying the need for testing for OSA. A laboratory sleep study with a PSG can confirm the diagnosis and severity of OSA. HSATs are available to confirm the diagnosis of OSA in patients at high risk for moderate to severe OSA.

DEFINITION

Obstructive sleep apnea (OSA) occurs when there are recurrent episodes of upper airway collapse and obstruction during sleep associated with arousals with or without oxygen desaturations. The oropharynx in the back of the throat collapses during OSA events to cause arousal or oxygen desaturation or both resulting in fragmented sleep.

PREVALENCE

Studies reveal OSA is prevalent. A 2015 study in Switzerland reported 50% of men and 23% of women had at least moderate OSA.¹ In 2002, the Sleep Heart Health study found that 24% of men and 9% of women have at least mild OSA.² In the Wisconsin Sleep Study Cohort, it was reported that 10% of men and 3% of women age 30 to 49 have at least moderate OSA, while 17% of men and 9% of women age 50 to 70 have at least moderate OSA.³ OSA is highly underrecognized and it is estimated that 82% of men and 93% of women in the United States with OSA are undiagnosed.⁴

SYMPTOMS

RISK FACTORS

The risk of OSA is influenced by unmodifiable and modifiable factors. Unmodifiable risk factors include male sex, age, and race. Genetic predisposition or a family history of OSA as well as cranial facial anatomy resulting in narrow airways may impart higher risk of OSA. Modifiable risk factors include obesity, medications that cause muscle relaxation and narrowing of the airway (opiates, benzodiazepines, alcohol), endocrine disorders (hypothyroidism, polycystic ovarian syndrome), smoking, and nasal congestion or obstruction.⁶

Sex

Men are at higher risk for OSA than women although once women reach menopause they have a risk similar to men. Postmenopausal women on hormone replacement therapy were found to have lower rates of OSA, suggesting that loss of hormones results in greater risk of OSA.^7,8 Women also have more OSA during rapid eye movement (REM) sleep and less OSA when sleeping supine, whereas most men have OSA when sleeping supine.^9,10 OSA is less severe in women compared with men of similar body mass index (BMI).¹¹ Symptoms vary in men and women: snoring and witnessed apneas are more common in men whereas insomnia and excessive daytime sleepiness are more common in women.¹¹ This may account for delayed diagnosis and the higher mortality in women compared with men.

Age

The risk of OSA increases with age. In a study of men 65 or older, the prevalence of moderate OSA was 23% in men younger than 72 and 30% in men older than 80.¹² By comparison, the prevalence of moderate OSA in men 30 to 40 years was 10%.³ Increased risk of OSA with age may be due to age-related reduction in slow wave sleep (ie, deep sleep), which is protective against sleep-disordered breathing and airway collapse.¹³ Older adults are also less symptomatic, reporting less daytime sleepiness and fatigue.¹⁴

Race

The Sleep Heart Health Study found a slightly increased risk of moderate to severe OSA in blacks (20%) and American Indians (23%) compared with whites (17%).² Another study showed the  prevalence of OSA was 30% in whites, 32% in blacks, 38% in Hispanics, and 39% in Chinese individuals.¹⁵ A higher prevalence of OSA in young blacks (≤ 25 years) compared with whites was reported,¹⁶ although another study found no differences based on race in older patients.¹⁷ These differences among racial groups may be due to variations in craniofacial anatomy.

Obesity

There is a correlation between increased risk of OSA and obesity (BMI > 30 kg/m²) and its correlates of greater waist-to-hip ratio and neck circumference.² A 10% increase in body weight results in a sixfold increase in moderate to severe OSA and increases the apnea–hypopnea index (AHI; number of breath pauses or respiratory events per hour) by 32% whereas a 10% decrease in weight decreases the AHI by 26%.¹⁸

COMORBIDITIES

OSA is associated with a number of comorbid conditions including stroke, myocardial infarction, hypertension, hyperlipidemia, glucose intolerance, diabetes, arrhythmias including atrial fibrillation, pulmonary hypertension, congestive heart failure, and depression. Patients with moderate or severe OSA are at higher risk of these comorbid conditions.¹⁹

Patients with cardiovascular disease have a very high prevalence of OSA: hypertension (83% mild to 30% moderate to severe OSA), heart failure (55% to 12%), arrhythmias (50% to 20%), stroke (75% to 57%), and coronary heart disease (65% to 38%).²⁰ Increased awareness and early diagnosis of OSA is critical to reducing cardiovascular disease burden.

Sleep history

A sleep history starts with determining the patient’s total sleep time, based on time to bed, time to fall asleep, and time of wake up, including any difficulty falling asleep, staying asleep, or daytime naps.

Symptoms. Daytime naps generally indicate a sleep deficit or sleep that is not refreshing. A review of sleep and daytime symptoms associated with OSA (Table 1) helps determine if excessive daytime sleepiness or unrefreshing sleep is out of proportion with the amount of sleep the patient is getting at night.

Some patients with OSA may have memory or concentration issues or feel like they have attention deficit disorder. In fact some patients are diagnosed with attention deficit disorder because of their insufficient sleep or unrefreshing sleep.

Drowsy driving is a special concern in patients with untreated OSA and sleep deprivation. Many patients have drowsy driving episodes or difficulty staying awake during long-distance driving. Caffeine use is also important information as excessive caffeine may be used to combat sleepiness during the day.

The Epworth Sleepiness Scale is a clinical screening tool that presents 8 situations for patients to consider and indicate their level of sleepiness and likelihood of falling asleep (never = 0; slight = 1; moderate = 2, high = 3).^21,22 A total score ≥ 10 is considered abnormal in that the patient is excessively sleepy compared with most people.

Risk factors and comorbid conditions. OSA risk factors and comorbidities, including a BMI obesity assessment, should be reviewed with patients. Nasal congestion or mouth breathing especially at night could be due to airway obstruction increasing the risk of OSA. Family history of OSA, tobacco, alcohol use, other medical conditions, and medications should also be discussed.

Physical examination

• Neck circumference greater than 17 inches for men or greater than 16 inches for women
• BMI greater than 30
• Friedman class tongue position class 3 or greater (Figure 1)
• Mouth features (present/enlarged tonsils, macroglossia, jaw misalignment)
• Nasal abnormalities (turbinate hypertrophy, deviated septum).⁵

Patients with Friedman palate positions class 3 and 4 have a higher risk of OSA due to airway crowding during sleep when the airway naturally collapses a little and is even more restricted.

Narrow airways or oropharyngeal crowding can also be due to a swollen, enlarged, or elongated uvula; present or enlarged tonsils; or lateral wall narrowing. Alone or in combination, these features can contribute to airway obstruction.

Other signs in the mouth suggestive of obstruction are macroglossia (enlarged tongue) and tongue ridging. Tongue ridging or scalloping impressions typically occur during sleep and are caused by the tongue moving forward to open the airway and pressing against the teeth.

Retrognathia (lower jaw offset behind upper jaw) can narrow the airway and increase the risk of OSA as can a high arch palate, overbite (upper teeth forward), or overjet (upper teeth over the top of lower teeth).

A nasal examination for nasal valve collapse (ie, nostril collapses with inhalation), deviated septum, and inferior turbinate hypertrophy impart an increased risk of OSA.

Screening tools

In addition to the Epworth Sleepiness Scale, the STOP-BANG questionnaire can help determine if a patient should be tested further for OSA. The STOP-BANG questionnaire consists of 8 yes-no questions where more than 2 yes responses indicate the patient is at higher risk for moderate to severe OSA (93% sensitivity): Snore, Tired, Observed stopped breathing, high blood Pressure, BMI > 35 kg/m², Age > 50, Neck > 15.75 inches, Gender = male).²³

Polysomnography

Home sleep apnea test

HSATs record 4 to 7 parameters including airflow (thermal and nasal pressure), effort (inductive ple­thysmography), and oximetry. No electroencephalogram is used, so sleep is not recorded; it is assumed the patient is sleeping for the duration of the test. As such, respiratory events are based on oxygen desaturations and reduced airflow and pressure as well as chest and abdomen effort. The raw data are edited and manually scored and reviewed by a sleep specialist.²⁵

Although the HSAT is convenient for many patients, it underestimates the severity of sleep-related breathing disorders. HSAT is intended to confirm OSA in patients with a high likelihood of OSA based on their sleep history.²⁶ It is ideally employed for adult patients with no major medical problems or other sleep problems who are at high risk for moderate to severe OSA based on the STOP-BANG questionnaire or those with daytime sleepiness and 2 of the 3 symptoms of snoring, witnessed apnea, or hypertension.²⁷

A negative or inconclusive HSAT warrants a PSG to ensure the patient does not have OSA. Use of HSAT is contraindicated in patients with

• Significant cardiopulmonary disease
• Potential weakness due to a neuro­muscular condition
• Awake hypoventilation or high risk for sleep-related hypoventilation (severe obesity)
• History of stroke
• Chronic opioid use
• Severe insomnia
• Symptoms of other significant sleep disorders
• Environmental/personal factors that would preclude adequate acquisition and interpretation of data (disruptions from children, pets, other factors).²⁷

DIAGNOSTIC CRITERIA

Respiratory events captured on a PSG or HSAT

The OSA diagnostic criteria are based on the occurrence of obstructive respiratory events recorded during sleep such as apneas, hypopneas, and respiratory event-related arousals.

Hypopneas. A hypopnea is a respiratory event resulting in reduced airflow. The America Association of Sleep Medicine’s preferred definition is a reduction in nasal pressure of at least 30% for 10 seconds or longer with 3% or greater oxygen desaturation or an electroencephalogram arousal. Another acceptable definition is at least 30% reduction in thoracoabdominal movement or airflow with 4% or greater oxygen desaturation, which is used by the Centers for Medicare and Medicaid Services and other insurers.^29,30 Hypopnea requires greater oxygen desaturation and is not dependent on arousals, which can sometimes make it more challenging to identify OSA (Figure 2).

Respiratory event-related arousals. Respiratory event-related arousals are respiratory events not meeting apnea or hypopnea criteria. They are measured as a sequence of breaths of 10 or more seconds with increasing respiratory effort or flattening of the nasal pressure waveform leading to arousal (Figure 2).²⁹ Respiratory event-related arousals are disruptive to sleep and have many of the same consequences as apneas and hypopneas.

Severity

SUMMARY

OSA results from airway collapse and obstruction during sleep, often causing arousal from sleep with or without oxygen desaturation. The prevalence of OSA is underestimated and it is underdiagnosed despite known risk factors and comorbid conditions. Screening for OSA with a sleep history, simple upper airway examination, and quick validated screening tool like the STOP-BANG or Epworth Sleepiness Scale aid in identifying the need for testing for OSA. A laboratory sleep study with a PSG can confirm the diagnosis and severity of OSA. HSATs are available to confirm the diagnosis of OSA in patients at high risk for moderate to severe OSA.

SLEEP AND CARDIOVASCULAR PHYSIOLOGY

Wakefullness and sleep, the latter comprised of non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep, comprise our primary states of being. Sleep states oscillate between NREM and REM sleep. The first and shortest period of REM sleep typically occurs 90 to 120 minutes into the sleep cycle. Most REM sleep, including the longest period of REM sleep, occurs during the latter part of the sleep cycle.

With these sleep state changes, physiologic changes also occur, such as reduced heart rate and blood pressure because of enhanced parasympathetic tone. During REM sleep, there are also intermittent sympathetic nervous system surges. Other physiologic changes include a regular respiratory rate during NREM sleep and an irregular respiratory rate during REM sleep. Body temperature is normal during NREM sleep and poikilothermic (ie, tends to flucuate) during REM sleep. Blood pressure is reduced 10% to 15% during sleep¹ and then rises, so that the highest blood pressure occurs in the morning. Data from 10 million users of activity-monitoring devices show that the heart rate changes during sleep.² The heart rate is decreased in those who get less than 7 hours of sleep, then increases with longer sleep duration in a U-shaped distribution.

Cardiovascular events are more likely to occur at certain times of day. Myocardial infarction is more likely in the morning, with a threefold increased risk within the first 3 hours of awakening that peaks around 9 AM.^3,4 Similar diurnal patterns have been observed with other cardiovascular conditions such as sudden cardiac death and ischemic episodes, with the highest risk during morning hours (6 to 9 AM).⁴

The reason for this morning predisposition for cardio­vascular events is unclear, but it is thought that perhaps the autonomic fluctuations that occur during REM sleep and the predominance of REM sleep in early morning may be a factor. Diurnal changes in blood pressure and cortisol levels may also contribute, as well as levels of systemic inflammatory and thrombotic markers such as plasminogen activator inhibitor 1.

Arrhythmias are also more likely to occur in a diurnal pattern. Atrial fibrillation (AF), particularly paroxysmal AF, is believed to be vagally mediated in 10% to 25% of patients.⁵ Therefore, for those who are predisposed, sleep may represent a period of increased risk for AF. In a study of individuals 60 years and older, the maximum duration and peak frequency of AF occurred from midnight to 2 AM.⁵

Recent studies have found that REM-related obstructive sleep apnea (OSA) is associated with increased cardiovascular risk. Experimental models show that REM sleep may increase the risk for compromised coronary blood flow.⁶ Increased heart rate corresponds to reduced coronary blood flow and thus, to decreased coronary perfusion time and less time for relaxation of the heart, increasing the risk for coronary artery disease, thrombosis, and ischemia.

SLEEP APNEA PATHOPHYSIOLOGY

The normal physiology of the sleep-heart inter­action is disrupted by sleep apnea. OSA is defined as episodes of complete or partial airway obstruction that occur during sleep with thoraco­abdominal effort. Central sleep apnea (CSA) is the cessation of breathing with no thoracoabdominal effort. The pathophysiology of the sleep-heart interaction varies for OSA and CSA.

Obstructive sleep apnea

OSA is a nocturnal physiologic stressor that is highly prevalent and underrecognized. It affects approximately 17% of the adult population, and the prevalence is increasing with the obesity epidemic. Nearly 1 in 15 individuals is estimated to be affected by at least moderate OSA.^7,8 OSA is underdiagnosed particularly in minority populations.⁹ Data from the 2015 Multi-Ethnic Study of Atherosclerosis (MESA) showed undiagnosed moderate to severe sleep apnea in 84% to 93% of individuals,⁹ similar to an estimated 85% of undiagnosed cases in 2002.¹⁰

OSA is highly prevalent in individuals with underlying coronary disease^11–13 and in those with cardiovascular risk factors such as diabetes, hypertension, and heart failure. The prevalence of OSA in patients with cardiovascular disease ranges from 30% (hypertension) to 60% (stroke or transient ischemic attack, arrhythmia, end-stage renal disease).¹⁴

The alterations in sympathetic activation that occur during sleep in patients with OSA persist during wakefulness. Microneurographic recording of sympathetic nerve activity in the peroneal nerve reveal that the rate of sympathetic bursts doubles and the amplitude is greater in individuals with OSA compared with a control group.¹⁵

Sympathetic nerve activity, blood pressure, and heart rate were shown to increase during REM sleep in individuals with OSA on continuous positive airway pressure (CPAP) during an induced apneic event (pressure reduction from 8 cm to 6 cm of water).¹⁵

During OSA episodes, there is an increased cardiac load. Impaired diastolic function and atrial and aortic enlargement, and in particular, the thin-walled atria are very susceptible to the intra­thoracic pressure swings caused by OSA. Physiologic changes with OSA from pressure changes in the chest result in shift of the intraventricular septum, causing a reduction in cardiac output.¹⁶ With the lowering of oxygen during episodes of apnea, constriction of the pulmonary vasculature leads to elevation of pressure in the pulmonary vasculature reflected by the increase in mean pulmonary arterial pressures.¹⁷

Other studies have shown that OSA increases upregulation of markers of systemic inflammation and prothrombotic markers, the very markers that can increase cardiovascular or atherogenic risk.^18–22 One example is the soluble interleukin 6 receptor, shown to be elevated in the morning relative to sleep apnea compared with the evening.²⁰ Other biomarkers observed to be associated with sleep apnea include markers of prothrombotic potentials such as plasminogen activator inhibitor 1.¹⁹ Oxidative stress occurs because intermittent bouts of lower oxygen can lead to oxidation of serum proteins and lipids. Endothelial dysfunction has been observed as well as insulin resistance and dyslipidemia.²³ Taken together, these are pathways that lead to atherogenesis and increased cardiovascular risk.

Central sleep apnea

CSA episodes are the cessation of breathing without thoracoabdominal effort, in contrast to the persistence of thoracoabdominal effort in OSA. CSA is characterized by breathing instability with highly sensitive chemoresponses and prolonged circulation time.²⁴ This can be physiologic in some cases, as when it occurs after a very large breath or sigh and then a central apnea event occurs after the sigh. The alterations in oxygen and CO₂ and the stretch of the receptors in the alveoli of the lungs initiate the Hering-Breuer inhalation reflex.

Pathophysiology of CSA

Complex pathways of medullary and aortic receptor chemosensitivity are at the root of the pathophysiology of CSA.²⁴ With CSA there is often a relative state of hypocapnia at baseline. During sleep, there is reduction in drive, thus chemo­sensitivity can be activated so that central apnea episodes can ensue as a result of alterations in CO₂ (ie, hypocapnia). Another factor that can contribute to the pathophysiology of CSA is arousal from sleep that can reduce CO₂ levels and therefore perpetuate central events.

The concept of loop gain is used to understand the pathophysiology of CSA. Loop gain is a measure of the relative stability of a ventilation system and indicates the likelihood of an individual to have periodic breathing. It is calculated by the response to a disturbance divided by the disturbance itself.²⁵ With a high loop gain, there is a more pronounced or exuberant response to the disturbance, indicating more instability in the system and increasing the tendency for irregular breathing and CSA episodes.

Hunter-Cheyne-Stokes respiration occurs with CSA and is characterized by cyclical crescendo-decrescendo respiratory effort that occurs during wakefulness and sleep without upper-airway obstruction.^26,27 Unlike OSA, which is worse during REM sleep, Hunter-Cheyne-Stokes breathing in CSA is typically worse in NREM sleep, during N1 and N2 in particular.

Both OSA and CSA are prevalent in patients with heart failure and may be associated with the progression of heart failure. CSA often occurs in patients with heart failure. The pathophysiology is multi­factorial, including pulmonary congestion that results in stretch of the J receptors in the alveoli, prolonged circulation time, and increased chemosensitivity.

Complex pathways in the neuroaxis or somnogenic biomarkers of inflammation or both may be implicated in the paradoxical lack of subjective sleepiness in the presence of increased objective measures of sleepiness in systolic heart failure. One study found a relationship with one biomarker of inflammation and oxidative stress as it relates to objective symptoms of sleepiness but not subjective symptoms of sleepiness.²⁸

Another contributing factor in the relationship between OSA and CSA in heart failure has also been described related to rostral shifts in fluid to the neck and to the pulmonary receptors in the alveoli of the lungs.²⁹ These rostral shifts in fluids may contribute to sleep apnea with parapharyngeal edema leading to OSA and pulmonary congestion leading to CSA.

Sleep apnea is associated with increased post-discharge mortality and hospitalization readmissions in the setting of acute heart failure.³⁰ Mortality analysis of 1,096 patients admitted for decompensated heart failure found CSA and OSA were independently associated with mortality in patients compared with patients with no or minimal sleep-disordered breathing.³⁰

CSA has also been shown to be a predictor of readmission in patients admitted for heart failure exacerbations.³¹ Targeting underlying CSA may reduce readmissions in those admitted with acute decompensated heart failure. While men were identified to be at increased risk of death relative to sleep-disordered breathing based on the initial results of the Sleep Heart Health Study, a subsequent epidemiologic substudy reflective of an older age group showed that OSA was more strongly associated with left ventricular mass index, risk of heart failure, or death in women compared with men.³²

Treatment

Standard therapy for treatment of OSA is CPAP. Adaptive servo-ventilation (ASV) and transvenous phrenic nerve stimulation are also available as treatment options in certain cases of CSA.

One of the first randomized controlled trials designed to assess the impact of CSA treatment on survival in patients with heart failure initially favored the control group then later the CPAP group and was terminated early based on stopping rules.^33,34 While adherence to therapy was suboptimal at an average of 3.6 hours, post hoc analysis showed that patients with CSA using CPAP with effective suppression of CSA had improved survival compared with patients who did not have effective suppression using CPAP.³⁴

ASV is mainly used for treatment of CSA. In ASV, positive airway pressure for ventilation support is provided and adjusts as apneic episodes are detected during sleep. The support provided adapts to the physiology of the patient and can deliver breaths and utilize anticyclic modes of ventilation to address crescendo-decrescendo breathing patterns observed in Hunter-Cheyne-Stokes respiration.

In the Treatment of Sleep-Disordered Breathing With Predominant Central Sleep Apnea by Adaptive Servo Ventilation in Patients With Heart Failure (SERVE-HF) trial, 1,300 patients with systolic heart failure and predominantly CSA were randomized to receive ASV vs solely standard medical management.³⁵ The primary composite end point included all-cause mortality or unplanned admission or hospitalization for heart failure. No difference was found in the primary end point between the ASV and the control group; however, there was an unanticipated negative impact of ASV on cardiovascular outcomes in some secondary end points. Based on the secondary outcome of cardiovascular-specific mortality, clinicians were advised that ASV was contraindicated for the treatment of CSA in patients with symptomatic heart failure with a left ventricular ejection fraction less than 45%. The interpretation of this study was complicated by several methodologic limitations.³⁶

The Cardiovascular Improvements With Minute Ventilation-Targeted Adaptive Servo-Ventilation Therapy in Heart Failure (CAT-HF) randomized controlled trial also evaluated ASV compared with standard medical management in 126 patients with heart failure.³⁷ This trial was terminated early because of the results of the SERVE-HF trial. Compliance with therapy was suboptimal at an average of 2.7 hours per day. The composite end point did not differ between the 2 groups; however, this was likely because the study was underpowered and was terminated early. Subgroup analysis revealed that patients with heart failure with preserved ejection fraction may benefit from ASV; however, additional studies are needed to confirm these findings.

Therefore, although ASV is not indicated when there is predominantly CSA in patients with systolic heart failure, preliminary results support potential benefit in patients with OSA and preserved ejection fraction.

Another novel treatment for CSA is transvenous phrenic nerve stimulation. A device is implanted that stimulates the phrenic nerve to initiate breaths. The initial study of trans­venous phrenic nerve stimulation reported a significant reduction in the number of episodes of central apnea per hour of sleep.^38,39 The apnea–hypopnea index improved overall and some types of obstructive apneic events were reduced with transvenous phrenic nerve stimulation.

A multicenter randomized control trial of trans­venous phrenic nerve stimulation found improvement in several sleep apnea indices, including central apnea, hypoxia, reduced arousals from sleep, and patient reported well-being.⁴⁰ Transvenous phrenic nerve stimulation holds promise as a novel therapy for central predominant sleep apnea not only in terms of improving the degree of central apnea and sleep-disordered breathing, but also in improving functional outcomes. Longitudinal and intereventional trial data are needed to clarify the impact of transvenous phrenic nerve stimulation on long-term cardiac outcomes.

SLEEP APNEA AND ATRIAL FIBRILLATION AND STROKE

Atrial fibrillation

AF is the most common sustained cardiac arrhythmia. The number of Americans with AF is projected to increase from 2.3 million to more than 10 million by the year 2050.⁴¹ The increasing incidence and prevalence of AF is not fully explained by the aging population and established risk factors.⁴² Unrecognized sleep apnea, estimated to exist in 85% or more of the population, may partially account for the increasing incidence of AF.⁴³

There are 3 types of AF, which are thought to follow a continuum: paroxysmal AF is characterized by episodes that occur intermittently; persistent AF is characterized by episodes that last longer than 7 days; chronic or permanent AF is typically characterized by AF that is ongoing over many years.⁴⁴ As with sleep apnea, AF is often asymptomatic and is likely underdiagnosed.

Sleep apnea and AF share several risk factors. Obesity is a risk factor for both OSA and AF; however, a meta-analysis supported a stronger association of OSA and AF vs obesity and AF.⁴⁵ Increasing age is a risk factor for both OSA and AF.^46,47 Although white populations are at higher risk for AF, OSA is associated with a 58% increased risk of AF in African Americans.⁴⁸ Nocturnal hypoxia has been associated with increased risk of AF in Asians.⁴⁹

Experimental data continue to accrue providing biologic plausibility of the relationship between sleep apnea and AF. OSA contributes to structural and electrical remodeling of the heart with evidence supporting increased fibrosis and electrical remodeling in patients with OSA compared with a control group.⁵¹ Markers of structural remodeling, such as atrial size, electrical silence, and atrial voltage conduction velocity, are altered in OSA.⁵⁰

Data from the Sleep Heart Health Study show very strong associations between atrial and ventricular cardiac arrhythmias and sleep apnea with two- to fivefold higher odds of arrhythmias in patients with severe OSA compared with controls even after accounting for confounding factors such as obesity.⁵²

A multicenter, epidemiological study of older men showed that increasing severity of sleep apnea corresponds with an increased prevalence of AF and ventricular ectopy.⁵³ This graded dose-response relationship suggests a causal relationship between sleep apnea and AF and ventricular ectopy. There also appears to be an immediate influence of apneic events and hypopneic events as it relates to arrhythmia. A case-crossover study showed an associated 18-fold increased risk of nocturnal arrhythmia within 90 seconds of an apneic or hypopneic event.⁵⁴ This association was found with paroxysms of AF and with episodes of nonsustained ventricular tachycardia.

Data from a clinic-based cohort study show an association between AF and OSA.⁵⁵ Specifically, increased severity of sleep apnea was associated with an increased prevalence of AF. Increasing degree of hypoxia or oxygen-lowering was also associated with increased incidence of AF or newly identified AF identified over time.

Longitudinal examination of 2 epidemiologic studies, the Sleep Heart Health Study and Outcomes of Sleep Disorders Study in Older Men, found CSA to be predictive of AF with a two- to threefold higher odds of developing incident AF as it related to baseline CSA.⁵⁶ According to these data, CSA may pose a greater risk for development of AF than OSA.

With respect to AF after cardiac surgery, patients with sleep apnea and obesity appear to be at higher risk for developing AF as measured by the apnea–hypopnea index and oxygen desaturation index.⁵⁷

Treatment of sleep apnea may improve arrhythmic burden. Case-based studies have shown reduced burden and resolution of baseline arrhythmia with CPAP treatment for OSA as therapeutic pressure was achieved.⁵⁸ Another case-based study involved an individual with snoring and OSA and AF at baseline.⁵⁹ Several retrospective studies have shown that treatment of OSA after ablation and after cardio­version results in reduced recurrence of AF; however, large definitive clinical trials are lacking.

Stroke

Sleep apnea is a risk factor for stroke due to intermittent hypoxia-mediated elevation of oxidative stress and systemic inflammation, hypercoaguability, and impairment of cerebral autoregulation.⁶⁰ However, the relationship may be bidirectional in that stroke may be a risk factor for sleep apnea in the post-stroke period. The prevalence of sleep apnea post-stroke has been reported to be up to 70%. CSA can occur in up to 26% during the post-stroke phase.⁶¹ Data are inconsistent in terms of the location and size of stroke and the risk of sleep apnea, though cerebrovascular neuronal damage to the brainstem and cortical areas are evident.⁶² In one study, the incidence of stroke appeared to increase with the severity of sleep apnea.⁶³ These findings were more pronounced in men than in women; however, this study may not have captured the increased cardiovascular risk in postmenopausal women. The Outcomes of Sleep Disorders in Older Men study found that severe hypoxia increased the incidence of stroke, and that hypoxia may be a predictor of newly diagnosed stroke in older men.⁶⁴ Although definitive clinical trials are underway, post-hoc propensity-score matched analysis from the Sleep Apnea Cardiovascular Endpoints (SAVE) study showed a lower stroke risk in those adherent to CPAP compared with the control group (HR=0.56, 95% CI: 0.30-0.90).⁶⁵

The association between sleep apnea and coronary artery disease and cardiovascular mortality was considered in a Spanish study of 1,500 patients followed for 10 years, which reported that CPAP therapy reduced cardiac events in patients with OSA.⁶⁶ Patients with sleep apnea had an increased risk of fatal myocardial infarction or stroke. Survival of patients treated for sleep apnea approached that of patients without OSA.

In a study of a racially diverse cohort, an association of physician diagnosed sleep apnea with cardiovascular events and survival was identified.⁶⁷ Diagnosed sleep apnea was estimated to confer a two- to threefold increase in various cardiovascular outcomes and all-cause mortality.

Punjabi NM, et al. Sleep-disordered breathing and mortality: a prospective cohort study. PLoS Med 2009; 6(8):e1000132.

The effect of treatment for sleep apnea on cardiovascular outcomes was the focus of a recent randomized controlled trial of nearly 3,000 participants with a mean follow-up of 4 years.65 Use of CPAP compared with usual care found no difference in cardiovascular outcomes. However, secondary analysis revealed a possible benefit of a lower risk of stroke with use of CPAP therapy. Several factors should be considered in interpreting these findings: ie, low adherence with CPAP therapy (3 hours), whether the study was sufficiently powered to detect a change in cardiovascular outcomes, and if the duration of follow-up was adequate. In terms of patient demographics and study generalizability, the study did not include patients with severe sleep apnea and hypoxia, and most participants were men, of Asian descent, with a mean body mass index of 28 kg/m2, and low levels of sleepiness at baseline.

SLEEP AND CARDIOVASCULAR PHYSIOLOGY

Wakefullness and sleep, the latter comprised of non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep, comprise our primary states of being. Sleep states oscillate between NREM and REM sleep. The first and shortest period of REM sleep typically occurs 90 to 120 minutes into the sleep cycle. Most REM sleep, including the longest period of REM sleep, occurs during the latter part of the sleep cycle.

With these sleep state changes, physiologic changes also occur, such as reduced heart rate and blood pressure because of enhanced parasympathetic tone. During REM sleep, there are also intermittent sympathetic nervous system surges. Other physiologic changes include a regular respiratory rate during NREM sleep and an irregular respiratory rate during REM sleep. Body temperature is normal during NREM sleep and poikilothermic (ie, tends to flucuate) during REM sleep. Blood pressure is reduced 10% to 15% during sleep¹ and then rises, so that the highest blood pressure occurs in the morning. Data from 10 million users of activity-monitoring devices show that the heart rate changes during sleep.² The heart rate is decreased in those who get less than 7 hours of sleep, then increases with longer sleep duration in a U-shaped distribution.

Cardiovascular events are more likely to occur at certain times of day. Myocardial infarction is more likely in the morning, with a threefold increased risk within the first 3 hours of awakening that peaks around 9 AM.^3,4 Similar diurnal patterns have been observed with other cardiovascular conditions such as sudden cardiac death and ischemic episodes, with the highest risk during morning hours (6 to 9 AM).⁴

The reason for this morning predisposition for cardio­vascular events is unclear, but it is thought that perhaps the autonomic fluctuations that occur during REM sleep and the predominance of REM sleep in early morning may be a factor. Diurnal changes in blood pressure and cortisol levels may also contribute, as well as levels of systemic inflammatory and thrombotic markers such as plasminogen activator inhibitor 1.

Arrhythmias are also more likely to occur in a diurnal pattern. Atrial fibrillation (AF), particularly paroxysmal AF, is believed to be vagally mediated in 10% to 25% of patients.⁵ Therefore, for those who are predisposed, sleep may represent a period of increased risk for AF. In a study of individuals 60 years and older, the maximum duration and peak frequency of AF occurred from midnight to 2 AM.⁵

Recent studies have found that REM-related obstructive sleep apnea (OSA) is associated with increased cardiovascular risk. Experimental models show that REM sleep may increase the risk for compromised coronary blood flow.⁶ Increased heart rate corresponds to reduced coronary blood flow and thus, to decreased coronary perfusion time and less time for relaxation of the heart, increasing the risk for coronary artery disease, thrombosis, and ischemia.

SLEEP APNEA PATHOPHYSIOLOGY

The normal physiology of the sleep-heart inter­action is disrupted by sleep apnea. OSA is defined as episodes of complete or partial airway obstruction that occur during sleep with thoraco­abdominal effort. Central sleep apnea (CSA) is the cessation of breathing with no thoracoabdominal effort. The pathophysiology of the sleep-heart interaction varies for OSA and CSA.

Obstructive sleep apnea

OSA is a nocturnal physiologic stressor that is highly prevalent and underrecognized. It affects approximately 17% of the adult population, and the prevalence is increasing with the obesity epidemic. Nearly 1 in 15 individuals is estimated to be affected by at least moderate OSA.^7,8 OSA is underdiagnosed particularly in minority populations.⁹ Data from the 2015 Multi-Ethnic Study of Atherosclerosis (MESA) showed undiagnosed moderate to severe sleep apnea in 84% to 93% of individuals,⁹ similar to an estimated 85% of undiagnosed cases in 2002.¹⁰

OSA is highly prevalent in individuals with underlying coronary disease^11–13 and in those with cardiovascular risk factors such as diabetes, hypertension, and heart failure. The prevalence of OSA in patients with cardiovascular disease ranges from 30% (hypertension) to 60% (stroke or transient ischemic attack, arrhythmia, end-stage renal disease).¹⁴

The alterations in sympathetic activation that occur during sleep in patients with OSA persist during wakefulness. Microneurographic recording of sympathetic nerve activity in the peroneal nerve reveal that the rate of sympathetic bursts doubles and the amplitude is greater in individuals with OSA compared with a control group.¹⁵

Sympathetic nerve activity, blood pressure, and heart rate were shown to increase during REM sleep in individuals with OSA on continuous positive airway pressure (CPAP) during an induced apneic event (pressure reduction from 8 cm to 6 cm of water).¹⁵

During OSA episodes, there is an increased cardiac load. Impaired diastolic function and atrial and aortic enlargement, and in particular, the thin-walled atria are very susceptible to the intra­thoracic pressure swings caused by OSA. Physiologic changes with OSA from pressure changes in the chest result in shift of the intraventricular septum, causing a reduction in cardiac output.¹⁶ With the lowering of oxygen during episodes of apnea, constriction of the pulmonary vasculature leads to elevation of pressure in the pulmonary vasculature reflected by the increase in mean pulmonary arterial pressures.¹⁷

Other studies have shown that OSA increases upregulation of markers of systemic inflammation and prothrombotic markers, the very markers that can increase cardiovascular or atherogenic risk.^18–22 One example is the soluble interleukin 6 receptor, shown to be elevated in the morning relative to sleep apnea compared with the evening.²⁰ Other biomarkers observed to be associated with sleep apnea include markers of prothrombotic potentials such as plasminogen activator inhibitor 1.¹⁹ Oxidative stress occurs because intermittent bouts of lower oxygen can lead to oxidation of serum proteins and lipids. Endothelial dysfunction has been observed as well as insulin resistance and dyslipidemia.²³ Taken together, these are pathways that lead to atherogenesis and increased cardiovascular risk.

Central sleep apnea

CSA episodes are the cessation of breathing without thoracoabdominal effort, in contrast to the persistence of thoracoabdominal effort in OSA. CSA is characterized by breathing instability with highly sensitive chemoresponses and prolonged circulation time.²⁴ This can be physiologic in some cases, as when it occurs after a very large breath or sigh and then a central apnea event occurs after the sigh. The alterations in oxygen and CO₂ and the stretch of the receptors in the alveoli of the lungs initiate the Hering-Breuer inhalation reflex.

Pathophysiology of CSA

Complex pathways of medullary and aortic receptor chemosensitivity are at the root of the pathophysiology of CSA.²⁴ With CSA there is often a relative state of hypocapnia at baseline. During sleep, there is reduction in drive, thus chemo­sensitivity can be activated so that central apnea episodes can ensue as a result of alterations in CO₂ (ie, hypocapnia). Another factor that can contribute to the pathophysiology of CSA is arousal from sleep that can reduce CO₂ levels and therefore perpetuate central events.

The concept of loop gain is used to understand the pathophysiology of CSA. Loop gain is a measure of the relative stability of a ventilation system and indicates the likelihood of an individual to have periodic breathing. It is calculated by the response to a disturbance divided by the disturbance itself.²⁵ With a high loop gain, there is a more pronounced or exuberant response to the disturbance, indicating more instability in the system and increasing the tendency for irregular breathing and CSA episodes.

Hunter-Cheyne-Stokes respiration occurs with CSA and is characterized by cyclical crescendo-decrescendo respiratory effort that occurs during wakefulness and sleep without upper-airway obstruction.^26,27 Unlike OSA, which is worse during REM sleep, Hunter-Cheyne-Stokes breathing in CSA is typically worse in NREM sleep, during N1 and N2 in particular.

Both OSA and CSA are prevalent in patients with heart failure and may be associated with the progression of heart failure. CSA often occurs in patients with heart failure. The pathophysiology is multi­factorial, including pulmonary congestion that results in stretch of the J receptors in the alveoli, prolonged circulation time, and increased chemosensitivity.

Complex pathways in the neuroaxis or somnogenic biomarkers of inflammation or both may be implicated in the paradoxical lack of subjective sleepiness in the presence of increased objective measures of sleepiness in systolic heart failure. One study found a relationship with one biomarker of inflammation and oxidative stress as it relates to objective symptoms of sleepiness but not subjective symptoms of sleepiness.²⁸

Another contributing factor in the relationship between OSA and CSA in heart failure has also been described related to rostral shifts in fluid to the neck and to the pulmonary receptors in the alveoli of the lungs.²⁹ These rostral shifts in fluids may contribute to sleep apnea with parapharyngeal edema leading to OSA and pulmonary congestion leading to CSA.

Sleep apnea is associated with increased post-discharge mortality and hospitalization readmissions in the setting of acute heart failure.³⁰ Mortality analysis of 1,096 patients admitted for decompensated heart failure found CSA and OSA were independently associated with mortality in patients compared with patients with no or minimal sleep-disordered breathing.³⁰

CSA has also been shown to be a predictor of readmission in patients admitted for heart failure exacerbations.³¹ Targeting underlying CSA may reduce readmissions in those admitted with acute decompensated heart failure. While men were identified to be at increased risk of death relative to sleep-disordered breathing based on the initial results of the Sleep Heart Health Study, a subsequent epidemiologic substudy reflective of an older age group showed that OSA was more strongly associated with left ventricular mass index, risk of heart failure, or death in women compared with men.³²

Treatment

Standard therapy for treatment of OSA is CPAP. Adaptive servo-ventilation (ASV) and transvenous phrenic nerve stimulation are also available as treatment options in certain cases of CSA.

One of the first randomized controlled trials designed to assess the impact of CSA treatment on survival in patients with heart failure initially favored the control group then later the CPAP group and was terminated early based on stopping rules.^33,34 While adherence to therapy was suboptimal at an average of 3.6 hours, post hoc analysis showed that patients with CSA using CPAP with effective suppression of CSA had improved survival compared with patients who did not have effective suppression using CPAP.³⁴

ASV is mainly used for treatment of CSA. In ASV, positive airway pressure for ventilation support is provided and adjusts as apneic episodes are detected during sleep. The support provided adapts to the physiology of the patient and can deliver breaths and utilize anticyclic modes of ventilation to address crescendo-decrescendo breathing patterns observed in Hunter-Cheyne-Stokes respiration.

In the Treatment of Sleep-Disordered Breathing With Predominant Central Sleep Apnea by Adaptive Servo Ventilation in Patients With Heart Failure (SERVE-HF) trial, 1,300 patients with systolic heart failure and predominantly CSA were randomized to receive ASV vs solely standard medical management.³⁵ The primary composite end point included all-cause mortality or unplanned admission or hospitalization for heart failure. No difference was found in the primary end point between the ASV and the control group; however, there was an unanticipated negative impact of ASV on cardiovascular outcomes in some secondary end points. Based on the secondary outcome of cardiovascular-specific mortality, clinicians were advised that ASV was contraindicated for the treatment of CSA in patients with symptomatic heart failure with a left ventricular ejection fraction less than 45%. The interpretation of this study was complicated by several methodologic limitations.³⁶

The Cardiovascular Improvements With Minute Ventilation-Targeted Adaptive Servo-Ventilation Therapy in Heart Failure (CAT-HF) randomized controlled trial also evaluated ASV compared with standard medical management in 126 patients with heart failure.³⁷ This trial was terminated early because of the results of the SERVE-HF trial. Compliance with therapy was suboptimal at an average of 2.7 hours per day. The composite end point did not differ between the 2 groups; however, this was likely because the study was underpowered and was terminated early. Subgroup analysis revealed that patients with heart failure with preserved ejection fraction may benefit from ASV; however, additional studies are needed to confirm these findings.

Therefore, although ASV is not indicated when there is predominantly CSA in patients with systolic heart failure, preliminary results support potential benefit in patients with OSA and preserved ejection fraction.

Another novel treatment for CSA is transvenous phrenic nerve stimulation. A device is implanted that stimulates the phrenic nerve to initiate breaths. The initial study of trans­venous phrenic nerve stimulation reported a significant reduction in the number of episodes of central apnea per hour of sleep.^38,39 The apnea–hypopnea index improved overall and some types of obstructive apneic events were reduced with transvenous phrenic nerve stimulation.

A multicenter randomized control trial of trans­venous phrenic nerve stimulation found improvement in several sleep apnea indices, including central apnea, hypoxia, reduced arousals from sleep, and patient reported well-being.⁴⁰ Transvenous phrenic nerve stimulation holds promise as a novel therapy for central predominant sleep apnea not only in terms of improving the degree of central apnea and sleep-disordered breathing, but also in improving functional outcomes. Longitudinal and intereventional trial data are needed to clarify the impact of transvenous phrenic nerve stimulation on long-term cardiac outcomes.

SLEEP APNEA AND ATRIAL FIBRILLATION AND STROKE

Atrial fibrillation

AF is the most common sustained cardiac arrhythmia. The number of Americans with AF is projected to increase from 2.3 million to more than 10 million by the year 2050.⁴¹ The increasing incidence and prevalence of AF is not fully explained by the aging population and established risk factors.⁴² Unrecognized sleep apnea, estimated to exist in 85% or more of the population, may partially account for the increasing incidence of AF.⁴³

There are 3 types of AF, which are thought to follow a continuum: paroxysmal AF is characterized by episodes that occur intermittently; persistent AF is characterized by episodes that last longer than 7 days; chronic or permanent AF is typically characterized by AF that is ongoing over many years.⁴⁴ As with sleep apnea, AF is often asymptomatic and is likely underdiagnosed.

Sleep apnea and AF share several risk factors. Obesity is a risk factor for both OSA and AF; however, a meta-analysis supported a stronger association of OSA and AF vs obesity and AF.⁴⁵ Increasing age is a risk factor for both OSA and AF.^46,47 Although white populations are at higher risk for AF, OSA is associated with a 58% increased risk of AF in African Americans.⁴⁸ Nocturnal hypoxia has been associated with increased risk of AF in Asians.⁴⁹

Experimental data continue to accrue providing biologic plausibility of the relationship between sleep apnea and AF. OSA contributes to structural and electrical remodeling of the heart with evidence supporting increased fibrosis and electrical remodeling in patients with OSA compared with a control group.⁵¹ Markers of structural remodeling, such as atrial size, electrical silence, and atrial voltage conduction velocity, are altered in OSA.⁵⁰

Data from the Sleep Heart Health Study show very strong associations between atrial and ventricular cardiac arrhythmias and sleep apnea with two- to fivefold higher odds of arrhythmias in patients with severe OSA compared with controls even after accounting for confounding factors such as obesity.⁵²

A multicenter, epidemiological study of older men showed that increasing severity of sleep apnea corresponds with an increased prevalence of AF and ventricular ectopy.⁵³ This graded dose-response relationship suggests a causal relationship between sleep apnea and AF and ventricular ectopy. There also appears to be an immediate influence of apneic events and hypopneic events as it relates to arrhythmia. A case-crossover study showed an associated 18-fold increased risk of nocturnal arrhythmia within 90 seconds of an apneic or hypopneic event.⁵⁴ This association was found with paroxysms of AF and with episodes of nonsustained ventricular tachycardia.

Data from a clinic-based cohort study show an association between AF and OSA.⁵⁵ Specifically, increased severity of sleep apnea was associated with an increased prevalence of AF. Increasing degree of hypoxia or oxygen-lowering was also associated with increased incidence of AF or newly identified AF identified over time.

Longitudinal examination of 2 epidemiologic studies, the Sleep Heart Health Study and Outcomes of Sleep Disorders Study in Older Men, found CSA to be predictive of AF with a two- to threefold higher odds of developing incident AF as it related to baseline CSA.⁵⁶ According to these data, CSA may pose a greater risk for development of AF than OSA.

With respect to AF after cardiac surgery, patients with sleep apnea and obesity appear to be at higher risk for developing AF as measured by the apnea–hypopnea index and oxygen desaturation index.⁵⁷

Treatment of sleep apnea may improve arrhythmic burden. Case-based studies have shown reduced burden and resolution of baseline arrhythmia with CPAP treatment for OSA as therapeutic pressure was achieved.⁵⁸ Another case-based study involved an individual with snoring and OSA and AF at baseline.⁵⁹ Several retrospective studies have shown that treatment of OSA after ablation and after cardio­version results in reduced recurrence of AF; however, large definitive clinical trials are lacking.

Stroke

Sleep apnea is a risk factor for stroke due to intermittent hypoxia-mediated elevation of oxidative stress and systemic inflammation, hypercoaguability, and impairment of cerebral autoregulation.⁶⁰ However, the relationship may be bidirectional in that stroke may be a risk factor for sleep apnea in the post-stroke period. The prevalence of sleep apnea post-stroke has been reported to be up to 70%. CSA can occur in up to 26% during the post-stroke phase.⁶¹ Data are inconsistent in terms of the location and size of stroke and the risk of sleep apnea, though cerebrovascular neuronal damage to the brainstem and cortical areas are evident.⁶² In one study, the incidence of stroke appeared to increase with the severity of sleep apnea.⁶³ These findings were more pronounced in men than in women; however, this study may not have captured the increased cardiovascular risk in postmenopausal women. The Outcomes of Sleep Disorders in Older Men study found that severe hypoxia increased the incidence of stroke, and that hypoxia may be a predictor of newly diagnosed stroke in older men.⁶⁴ Although definitive clinical trials are underway, post-hoc propensity-score matched analysis from the Sleep Apnea Cardiovascular Endpoints (SAVE) study showed a lower stroke risk in those adherent to CPAP compared with the control group (HR=0.56, 95% CI: 0.30-0.90).⁶⁵

The association between sleep apnea and coronary artery disease and cardiovascular mortality was considered in a Spanish study of 1,500 patients followed for 10 years, which reported that CPAP therapy reduced cardiac events in patients with OSA.⁶⁶ Patients with sleep apnea had an increased risk of fatal myocardial infarction or stroke. Survival of patients treated for sleep apnea approached that of patients without OSA.

In a study of a racially diverse cohort, an association of physician diagnosed sleep apnea with cardiovascular events and survival was identified.⁶⁷ Diagnosed sleep apnea was estimated to confer a two- to threefold increase in various cardiovascular outcomes and all-cause mortality.

Punjabi NM, et al. Sleep-disordered breathing and mortality: a prospective cohort study. PLoS Med 2009; 6(8):e1000132.

The effect of treatment for sleep apnea on cardiovascular outcomes was the focus of a recent randomized controlled trial of nearly 3,000 participants with a mean follow-up of 4 years.65 Use of CPAP compared with usual care found no difference in cardiovascular outcomes. However, secondary analysis revealed a possible benefit of a lower risk of stroke with use of CPAP therapy. Several factors should be considered in interpreting these findings: ie, low adherence with CPAP therapy (3 hours), whether the study was sufficiently powered to detect a change in cardiovascular outcomes, and if the duration of follow-up was adequate. In terms of patient demographics and study generalizability, the study did not include patients with severe sleep apnea and hypoxia, and most participants were men, of Asian descent, with a mean body mass index of 28 kg/m2, and low levels of sleepiness at baseline.

SLEEP AND CARDIOVASCULAR PHYSIOLOGY

Wakefullness and sleep, the latter comprised of non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep, comprise our primary states of being. Sleep states oscillate between NREM and REM sleep. The first and shortest period of REM sleep typically occurs 90 to 120 minutes into the sleep cycle. Most REM sleep, including the longest period of REM sleep, occurs during the latter part of the sleep cycle.

With these sleep state changes, physiologic changes also occur, such as reduced heart rate and blood pressure because of enhanced parasympathetic tone. During REM sleep, there are also intermittent sympathetic nervous system surges. Other physiologic changes include a regular respiratory rate during NREM sleep and an irregular respiratory rate during REM sleep. Body temperature is normal during NREM sleep and poikilothermic (ie, tends to flucuate) during REM sleep. Blood pressure is reduced 10% to 15% during sleep¹ and then rises, so that the highest blood pressure occurs in the morning. Data from 10 million users of activity-monitoring devices show that the heart rate changes during sleep.² The heart rate is decreased in those who get less than 7 hours of sleep, then increases with longer sleep duration in a U-shaped distribution.

Cardiovascular events are more likely to occur at certain times of day. Myocardial infarction is more likely in the morning, with a threefold increased risk within the first 3 hours of awakening that peaks around 9 AM.^3,4 Similar diurnal patterns have been observed with other cardiovascular conditions such as sudden cardiac death and ischemic episodes, with the highest risk during morning hours (6 to 9 AM).⁴

The reason for this morning predisposition for cardio­vascular events is unclear, but it is thought that perhaps the autonomic fluctuations that occur during REM sleep and the predominance of REM sleep in early morning may be a factor. Diurnal changes in blood pressure and cortisol levels may also contribute, as well as levels of systemic inflammatory and thrombotic markers such as plasminogen activator inhibitor 1.

Arrhythmias are also more likely to occur in a diurnal pattern. Atrial fibrillation (AF), particularly paroxysmal AF, is believed to be vagally mediated in 10% to 25% of patients.⁵ Therefore, for those who are predisposed, sleep may represent a period of increased risk for AF. In a study of individuals 60 years and older, the maximum duration and peak frequency of AF occurred from midnight to 2 AM.⁵

Recent studies have found that REM-related obstructive sleep apnea (OSA) is associated with increased cardiovascular risk. Experimental models show that REM sleep may increase the risk for compromised coronary blood flow.⁶ Increased heart rate corresponds to reduced coronary blood flow and thus, to decreased coronary perfusion time and less time for relaxation of the heart, increasing the risk for coronary artery disease, thrombosis, and ischemia.

SLEEP APNEA PATHOPHYSIOLOGY

The normal physiology of the sleep-heart inter­action is disrupted by sleep apnea. OSA is defined as episodes of complete or partial airway obstruction that occur during sleep with thoraco­abdominal effort. Central sleep apnea (CSA) is the cessation of breathing with no thoracoabdominal effort. The pathophysiology of the sleep-heart interaction varies for OSA and CSA.

Obstructive sleep apnea

OSA is a nocturnal physiologic stressor that is highly prevalent and underrecognized. It affects approximately 17% of the adult population, and the prevalence is increasing with the obesity epidemic. Nearly 1 in 15 individuals is estimated to be affected by at least moderate OSA.^7,8 OSA is underdiagnosed particularly in minority populations.⁹ Data from the 2015 Multi-Ethnic Study of Atherosclerosis (MESA) showed undiagnosed moderate to severe sleep apnea in 84% to 93% of individuals,⁹ similar to an estimated 85% of undiagnosed cases in 2002.¹⁰

OSA is highly prevalent in individuals with underlying coronary disease^11–13 and in those with cardiovascular risk factors such as diabetes, hypertension, and heart failure. The prevalence of OSA in patients with cardiovascular disease ranges from 30% (hypertension) to 60% (stroke or transient ischemic attack, arrhythmia, end-stage renal disease).¹⁴

The alterations in sympathetic activation that occur during sleep in patients with OSA persist during wakefulness. Microneurographic recording of sympathetic nerve activity in the peroneal nerve reveal that the rate of sympathetic bursts doubles and the amplitude is greater in individuals with OSA compared with a control group.¹⁵

Sympathetic nerve activity, blood pressure, and heart rate were shown to increase during REM sleep in individuals with OSA on continuous positive airway pressure (CPAP) during an induced apneic event (pressure reduction from 8 cm to 6 cm of water).¹⁵

During OSA episodes, there is an increased cardiac load. Impaired diastolic function and atrial and aortic enlargement, and in particular, the thin-walled atria are very susceptible to the intra­thoracic pressure swings caused by OSA. Physiologic changes with OSA from pressure changes in the chest result in shift of the intraventricular septum, causing a reduction in cardiac output.¹⁶ With the lowering of oxygen during episodes of apnea, constriction of the pulmonary vasculature leads to elevation of pressure in the pulmonary vasculature reflected by the increase in mean pulmonary arterial pressures.¹⁷

Other studies have shown that OSA increases upregulation of markers of systemic inflammation and prothrombotic markers, the very markers that can increase cardiovascular or atherogenic risk.^18–22 One example is the soluble interleukin 6 receptor, shown to be elevated in the morning relative to sleep apnea compared with the evening.²⁰ Other biomarkers observed to be associated with sleep apnea include markers of prothrombotic potentials such as plasminogen activator inhibitor 1.¹⁹ Oxidative stress occurs because intermittent bouts of lower oxygen can lead to oxidation of serum proteins and lipids. Endothelial dysfunction has been observed as well as insulin resistance and dyslipidemia.²³ Taken together, these are pathways that lead to atherogenesis and increased cardiovascular risk.

Central sleep apnea

CSA episodes are the cessation of breathing without thoracoabdominal effort, in contrast to the persistence of thoracoabdominal effort in OSA. CSA is characterized by breathing instability with highly sensitive chemoresponses and prolonged circulation time.²⁴ This can be physiologic in some cases, as when it occurs after a very large breath or sigh and then a central apnea event occurs after the sigh. The alterations in oxygen and CO₂ and the stretch of the receptors in the alveoli of the lungs initiate the Hering-Breuer inhalation reflex.

Pathophysiology of CSA

Complex pathways of medullary and aortic receptor chemosensitivity are at the root of the pathophysiology of CSA.²⁴ With CSA there is often a relative state of hypocapnia at baseline. During sleep, there is reduction in drive, thus chemo­sensitivity can be activated so that central apnea episodes can ensue as a result of alterations in CO₂ (ie, hypocapnia). Another factor that can contribute to the pathophysiology of CSA is arousal from sleep that can reduce CO₂ levels and therefore perpetuate central events.

The concept of loop gain is used to understand the pathophysiology of CSA. Loop gain is a measure of the relative stability of a ventilation system and indicates the likelihood of an individual to have periodic breathing. It is calculated by the response to a disturbance divided by the disturbance itself.²⁵ With a high loop gain, there is a more pronounced or exuberant response to the disturbance, indicating more instability in the system and increasing the tendency for irregular breathing and CSA episodes.

Hunter-Cheyne-Stokes respiration occurs with CSA and is characterized by cyclical crescendo-decrescendo respiratory effort that occurs during wakefulness and sleep without upper-airway obstruction.^26,27 Unlike OSA, which is worse during REM sleep, Hunter-Cheyne-Stokes breathing in CSA is typically worse in NREM sleep, during N1 and N2 in particular.

Both OSA and CSA are prevalent in patients with heart failure and may be associated with the progression of heart failure. CSA often occurs in patients with heart failure. The pathophysiology is multi­factorial, including pulmonary congestion that results in stretch of the J receptors in the alveoli, prolonged circulation time, and increased chemosensitivity.

Complex pathways in the neuroaxis or somnogenic biomarkers of inflammation or both may be implicated in the paradoxical lack of subjective sleepiness in the presence of increased objective measures of sleepiness in systolic heart failure. One study found a relationship with one biomarker of inflammation and oxidative stress as it relates to objective symptoms of sleepiness but not subjective symptoms of sleepiness.²⁸

Another contributing factor in the relationship between OSA and CSA in heart failure has also been described related to rostral shifts in fluid to the neck and to the pulmonary receptors in the alveoli of the lungs.²⁹ These rostral shifts in fluids may contribute to sleep apnea with parapharyngeal edema leading to OSA and pulmonary congestion leading to CSA.

Sleep apnea is associated with increased post-discharge mortality and hospitalization readmissions in the setting of acute heart failure.³⁰ Mortality analysis of 1,096 patients admitted for decompensated heart failure found CSA and OSA were independently associated with mortality in patients compared with patients with no or minimal sleep-disordered breathing.³⁰

CSA has also been shown to be a predictor of readmission in patients admitted for heart failure exacerbations.³¹ Targeting underlying CSA may reduce readmissions in those admitted with acute decompensated heart failure. While men were identified to be at increased risk of death relative to sleep-disordered breathing based on the initial results of the Sleep Heart Health Study, a subsequent epidemiologic substudy reflective of an older age group showed that OSA was more strongly associated with left ventricular mass index, risk of heart failure, or death in women compared with men.³²

Treatment

Standard therapy for treatment of OSA is CPAP. Adaptive servo-ventilation (ASV) and transvenous phrenic nerve stimulation are also available as treatment options in certain cases of CSA.

One of the first randomized controlled trials designed to assess the impact of CSA treatment on survival in patients with heart failure initially favored the control group then later the CPAP group and was terminated early based on stopping rules.^33,34 While adherence to therapy was suboptimal at an average of 3.6 hours, post hoc analysis showed that patients with CSA using CPAP with effective suppression of CSA had improved survival compared with patients who did not have effective suppression using CPAP.³⁴

ASV is mainly used for treatment of CSA. In ASV, positive airway pressure for ventilation support is provided and adjusts as apneic episodes are detected during sleep. The support provided adapts to the physiology of the patient and can deliver breaths and utilize anticyclic modes of ventilation to address crescendo-decrescendo breathing patterns observed in Hunter-Cheyne-Stokes respiration.

In the Treatment of Sleep-Disordered Breathing With Predominant Central Sleep Apnea by Adaptive Servo Ventilation in Patients With Heart Failure (SERVE-HF) trial, 1,300 patients with systolic heart failure and predominantly CSA were randomized to receive ASV vs solely standard medical management.³⁵ The primary composite end point included all-cause mortality or unplanned admission or hospitalization for heart failure. No difference was found in the primary end point between the ASV and the control group; however, there was an unanticipated negative impact of ASV on cardiovascular outcomes in some secondary end points. Based on the secondary outcome of cardiovascular-specific mortality, clinicians were advised that ASV was contraindicated for the treatment of CSA in patients with symptomatic heart failure with a left ventricular ejection fraction less than 45%. The interpretation of this study was complicated by several methodologic limitations.³⁶

The Cardiovascular Improvements With Minute Ventilation-Targeted Adaptive Servo-Ventilation Therapy in Heart Failure (CAT-HF) randomized controlled trial also evaluated ASV compared with standard medical management in 126 patients with heart failure.³⁷ This trial was terminated early because of the results of the SERVE-HF trial. Compliance with therapy was suboptimal at an average of 2.7 hours per day. The composite end point did not differ between the 2 groups; however, this was likely because the study was underpowered and was terminated early. Subgroup analysis revealed that patients with heart failure with preserved ejection fraction may benefit from ASV; however, additional studies are needed to confirm these findings.

Therefore, although ASV is not indicated when there is predominantly CSA in patients with systolic heart failure, preliminary results support potential benefit in patients with OSA and preserved ejection fraction.

Another novel treatment for CSA is transvenous phrenic nerve stimulation. A device is implanted that stimulates the phrenic nerve to initiate breaths. The initial study of trans­venous phrenic nerve stimulation reported a significant reduction in the number of episodes of central apnea per hour of sleep.^38,39 The apnea–hypopnea index improved overall and some types of obstructive apneic events were reduced with transvenous phrenic nerve stimulation.

A multicenter randomized control trial of trans­venous phrenic nerve stimulation found improvement in several sleep apnea indices, including central apnea, hypoxia, reduced arousals from sleep, and patient reported well-being.⁴⁰ Transvenous phrenic nerve stimulation holds promise as a novel therapy for central predominant sleep apnea not only in terms of improving the degree of central apnea and sleep-disordered breathing, but also in improving functional outcomes. Longitudinal and intereventional trial data are needed to clarify the impact of transvenous phrenic nerve stimulation on long-term cardiac outcomes.

SLEEP APNEA AND ATRIAL FIBRILLATION AND STROKE

Atrial fibrillation

AF is the most common sustained cardiac arrhythmia. The number of Americans with AF is projected to increase from 2.3 million to more than 10 million by the year 2050.⁴¹ The increasing incidence and prevalence of AF is not fully explained by the aging population and established risk factors.⁴² Unrecognized sleep apnea, estimated to exist in 85% or more of the population, may partially account for the increasing incidence of AF.⁴³

There are 3 types of AF, which are thought to follow a continuum: paroxysmal AF is characterized by episodes that occur intermittently; persistent AF is characterized by episodes that last longer than 7 days; chronic or permanent AF is typically characterized by AF that is ongoing over many years.⁴⁴ As with sleep apnea, AF is often asymptomatic and is likely underdiagnosed.

Sleep apnea and AF share several risk factors. Obesity is a risk factor for both OSA and AF; however, a meta-analysis supported a stronger association of OSA and AF vs obesity and AF.⁴⁵ Increasing age is a risk factor for both OSA and AF.^46,47 Although white populations are at higher risk for AF, OSA is associated with a 58% increased risk of AF in African Americans.⁴⁸ Nocturnal hypoxia has been associated with increased risk of AF in Asians.⁴⁹

Experimental data continue to accrue providing biologic plausibility of the relationship between sleep apnea and AF. OSA contributes to structural and electrical remodeling of the heart with evidence supporting increased fibrosis and electrical remodeling in patients with OSA compared with a control group.⁵¹ Markers of structural remodeling, such as atrial size, electrical silence, and atrial voltage conduction velocity, are altered in OSA.⁵⁰

Data from the Sleep Heart Health Study show very strong associations between atrial and ventricular cardiac arrhythmias and sleep apnea with two- to fivefold higher odds of arrhythmias in patients with severe OSA compared with controls even after accounting for confounding factors such as obesity.⁵²

A multicenter, epidemiological study of older men showed that increasing severity of sleep apnea corresponds with an increased prevalence of AF and ventricular ectopy.⁵³ This graded dose-response relationship suggests a causal relationship between sleep apnea and AF and ventricular ectopy. There also appears to be an immediate influence of apneic events and hypopneic events as it relates to arrhythmia. A case-crossover study showed an associated 18-fold increased risk of nocturnal arrhythmia within 90 seconds of an apneic or hypopneic event.⁵⁴ This association was found with paroxysms of AF and with episodes of nonsustained ventricular tachycardia.

Data from a clinic-based cohort study show an association between AF and OSA.⁵⁵ Specifically, increased severity of sleep apnea was associated with an increased prevalence of AF. Increasing degree of hypoxia or oxygen-lowering was also associated with increased incidence of AF or newly identified AF identified over time.

Longitudinal examination of 2 epidemiologic studies, the Sleep Heart Health Study and Outcomes of Sleep Disorders Study in Older Men, found CSA to be predictive of AF with a two- to threefold higher odds of developing incident AF as it related to baseline CSA.⁵⁶ According to these data, CSA may pose a greater risk for development of AF than OSA.

With respect to AF after cardiac surgery, patients with sleep apnea and obesity appear to be at higher risk for developing AF as measured by the apnea–hypopnea index and oxygen desaturation index.⁵⁷

Treatment of sleep apnea may improve arrhythmic burden. Case-based studies have shown reduced burden and resolution of baseline arrhythmia with CPAP treatment for OSA as therapeutic pressure was achieved.⁵⁸ Another case-based study involved an individual with snoring and OSA and AF at baseline.⁵⁹ Several retrospective studies have shown that treatment of OSA after ablation and after cardio­version results in reduced recurrence of AF; however, large definitive clinical trials are lacking.

Stroke

Sleep apnea is a risk factor for stroke due to intermittent hypoxia-mediated elevation of oxidative stress and systemic inflammation, hypercoaguability, and impairment of cerebral autoregulation.⁶⁰ However, the relationship may be bidirectional in that stroke may be a risk factor for sleep apnea in the post-stroke period. The prevalence of sleep apnea post-stroke has been reported to be up to 70%. CSA can occur in up to 26% during the post-stroke phase.⁶¹ Data are inconsistent in terms of the location and size of stroke and the risk of sleep apnea, though cerebrovascular neuronal damage to the brainstem and cortical areas are evident.⁶² In one study, the incidence of stroke appeared to increase with the severity of sleep apnea.⁶³ These findings were more pronounced in men than in women; however, this study may not have captured the increased cardiovascular risk in postmenopausal women. The Outcomes of Sleep Disorders in Older Men study found that severe hypoxia increased the incidence of stroke, and that hypoxia may be a predictor of newly diagnosed stroke in older men.⁶⁴ Although definitive clinical trials are underway, post-hoc propensity-score matched analysis from the Sleep Apnea Cardiovascular Endpoints (SAVE) study showed a lower stroke risk in those adherent to CPAP compared with the control group (HR=0.56, 95% CI: 0.30-0.90).⁶⁵

The association between sleep apnea and coronary artery disease and cardiovascular mortality was considered in a Spanish study of 1,500 patients followed for 10 years, which reported that CPAP therapy reduced cardiac events in patients with OSA.⁶⁶ Patients with sleep apnea had an increased risk of fatal myocardial infarction or stroke. Survival of patients treated for sleep apnea approached that of patients without OSA.

In a study of a racially diverse cohort, an association of physician diagnosed sleep apnea with cardiovascular events and survival was identified.⁶⁷ Diagnosed sleep apnea was estimated to confer a two- to threefold increase in various cardiovascular outcomes and all-cause mortality.

Punjabi NM, et al. Sleep-disordered breathing and mortality: a prospective cohort study. PLoS Med 2009; 6(8):e1000132.

The effect of treatment for sleep apnea on cardiovascular outcomes was the focus of a recent randomized controlled trial of nearly 3,000 participants with a mean follow-up of 4 years.65 Use of CPAP compared with usual care found no difference in cardiovascular outcomes. However, secondary analysis revealed a possible benefit of a lower risk of stroke with use of CPAP therapy. Several factors should be considered in interpreting these findings: ie, low adherence with CPAP therapy (3 hours), whether the study was sufficiently powered to detect a change in cardiovascular outcomes, and if the duration of follow-up was adequate. In terms of patient demographics and study generalizability, the study did not include patients with severe sleep apnea and hypoxia, and most participants were men, of Asian descent, with a mean body mass index of 28 kg/m2, and low levels of sleepiness at baseline.

Obstructive sleep apnea (OSA) is a serious condition that impacts quality of life and causes drowsy driving and depression. Research also reveals an interrelationship between OSA and metabolic disease and an association between OSA and cognitive impairment.

The diagnostic criteria of OSA are based on the number of apneic or hypopneic episodes per hour of sleep, called the apnea–hypopnea index (AHI) as recorded during sleep testing. Diagnosis of OSA is warranted if the AHI is 15 or more per hour or if the AHI is 5 or more per hour with 1 or more of the following features: sleepiness; nonrestorative sleep; fatigue or insomnia; waking up with breath-holding spells, gasping, or choking; snoring or breathing interruptions; or a coexisting diagnosis of hypertension, mood disorder, cognitive dysfunction, coronary artery disease, stroke, congestive heart failure, atrial fibrillation, or type II diabetes.¹

Many patients with an AHI less than 15 may also have OSA, given the number of coexisting medical conditions included in the OSA diagnostic criteria. Heart conditions such as coronary artery disease, atrial fibrillation, and congestive heart failure encompassed in the OSA diagnostic criteria have increased awareness of the link between OSA and heart health. Less well-known, and the subject of this review, are the negative consequences of OSA, particularly poor quality of life, drowsy driving, depression, metabolic disease, and cognitive impairment.

QUALITY OF LIFE

Reduced quality of life is the most fundamental patient-reported outcome of OSA. OSA is associated with excessive daytime sleepiness, inattention, and fatigue, which increase the risk of accidents and medical disability. These quality-of-life impairments are often the main reason patients seek medical care for sleep disorders.² Improved quality of life is a central goal of OSA treatment and is the best indicator of the effectiveness of treatment.³ Sleep health and its effect on quality of life is an area of focus of Healthy People 2020 (healthypeople.gov).

The American Academy of Sleep Medicine identified quality of life, along with detection of disease and cardiovascular consequences, as an outcome measure for assessing the quality of care for adults with OSA.² The assessment of quality of life for patients with OSA is a 4-part process: use evidence-based therapy, monitor the therapy, assess symptoms with a validated tool such as Epworth Sleepiness Scale, and assess the incidence of motor vehicle accidents. Information from these 4 processes can inform changes in a patient’s quality of life.

Treatment for OSA has been shown to improve quality of life. A study of 2,027 patients with OSA evaluated therapy adherence relative to mean Functional Outcomes of Sleep Questionnaire and European Quality of Life-5D scores.⁴ In patients with the most impaired quality of life, those adherent to positive airway pressure (PAP) therapy had improved quality of life as measured by these scores.

With respect to sleepiness, a systematic review of continuous PAP (CPAP) in patients with OSA found a 2.7-point reduction (mean difference; 95% confidence interval 3.45–1.96) in the Epworth Sleepiness Scale in patients using CPAP compared with the control group.⁵ Treatment of OSA improves patient quality of life and symptoms such as sleepiness.

DROWSY DRIVING

Drowsy driving by people with OSA can lead to motor vehicle accidents, which result in economic and health burdens.^6,7 National Center for Statistics and Analysis data reveal that of 6 million motor vehicle accidents (5-year average, 2005–2009), 1.4% involve drowsy driving and 2.5% of fatal crashes involve drowsy driving.⁸ Among noncommercial drivers, untreated OSA increases the risk of motor vehicle accidents 3- to 13-fold.⁹ The odds ratio of traffic accidents in drivers with untreated OSA is 6 times greater than in the general population.⁷

In a study of men and women in the general population (N = 913), individuals with moderate to severe OSA (AHI > 15) were more likely to have multiple motor vehicle accidents in the course of 5 years (odds ratio = 7.3) compared with those with no sleep-disordered breathing.¹⁰ The association between OSA and motor vehicle accidents is independent of sleepiness, and drivers with OSA may not perceive performance impairment.

There are 2 main reasons OSA increases the risk and incidence of motor vehicle accidents. OSA causes changes in attention and vigilance resulting from sleep deprivation and fragmentation. OSA also affects global cognition function, which may be due to intermittent hypoxia attributable to OSA.²

Treatment for OSA is effective in reducing the incidence of motor vehicle accidents. One study found the risk of motor vehicle accidents was eliminated with the use of CPAP treatment in patients with OSA.¹¹ A recent study of nearly 2,000 patients with OSA found a reduction in self-reported near-accidents from 14% before PAP therapy to 5.3% after starting PAP therapy.¹²

Estimates of the prevalence of depression in patients with OSA range from 5% to 63%.^13,14 One year after patients were diagnosed with OSA, the incidence of depression per 1,000 person-years was 18% compared with 8% in a group without OSA.¹⁴ Women with OSA reportedly have a higher risk of depression (adjusted hazard ratio [HR] 2.7) than men (HR 1.81) at 1-year follow-up.¹⁴ In the same study, with respect to age, there was no significant relationship noted between OSA and patients over age 64.

A one-level increase in the severity of OSA (ie, from minimal to mild) is associated with a nearly twofold increase in the adjusted odds for depression.¹⁵ On the other hand, studies have also found that patients on antidepressants may have an increased risk of OSA.¹⁶

Several potential mechanisms have been proposed to explain the link between depression and OSA.¹³ Poor-quality sleep, frequent arousal, and fragmentation of sleep in OSA may lead to frontal lobe emotional modulation changes. Intermittent hypoxia in OSA may result in neuronal injury and disruption of noradrenergic and dopaminergic pathways. Pro-inflammatory substances such as interleukin 6 and interleukin 1 are increased in OSA and depression and are mediators between both conditions. Neurotransmitters may be affected by a disrupted sleep-wake cycle. And serotonin, which may be impeded in depression, could influence the upper-airway dilator motor neurons.

Treatment of OSA improves symptoms of depression as measured by the Patient Health Questionnaire (PHQ-9). After 3 months of compliance with CPAP therapy, mean PHQ-9 scores decreased from 11.3 to 2.7 in a study of 228 patients with OSA.¹⁷ A study of 1,981 patients with sleep-disordered breathing found improved PHQ-9 scores in patients compliant with CPAP therapy and a greater improvement in patients with a baseline PHQ-9 higher than 10 (moderate severity).¹⁸

METABOLIC SYNDROME

OSA is associated with metabolic disorders, including metabolic syndrome, though the causality between these 2 conditions is yet to be illuminated. Metabolic syndrome is a term used when an individual has 3 or more of the following features or conditions:

• Waist circumference greater than 40 inches (men), greater than 35 inches (women)
• Triglycerides 150 mg/dL or greater or treatment for hypertriglyceridemia
• High-density lipoprotein cholesterol less than 40 mg/dL (men), less than 50 mg/dL (women), or treatment for cholesterol
• Blood pressure 130/85 mm Hg or greater, or treatment for hypertension
• Fasting blood glucose 100 mg/dL or greater, or treatment for hyperglycemia.¹⁹

Metabolic syndrome increases an individual’s risk of diabetes and cardiovascular disease and overall mortality. Like OSA, the prevalence of metabolic syndrome increases with age in both men and women.^20,21 The risk of metabolic syndrome is greater with more severe OSA. The Wisconsin Sleep Cohort (N = 546) reported an odds ratio for having metabolic syndrome of 2.5 for patients with mild OSA and 2.2 for patients with moderate or severe OSA.²² A meta-analysis also found a 2.4 times higher odds of metabolic syndrome in patients with mild OSA, but a 3.5 times higher odds of metabolic syndrome in patients with moderate to severe OSA compared with the control group.²³

Patients with both OSA and metabolic syndrome are said to have syndrome Z²⁴ and are at increased risk of cardiovascular morbidity and mortality.²⁵ Syndrome Z imparts a higher risk of atherogenic burden and prevalence of atheroma compared with patients with either condition alone.²⁶ In comparing patients with metabolic syndrome with and without OSA, those with OSA had increased atherosclerotic burden as measured by intima-media thickness and carotid femoral pulse-wave velocity.²⁷ Syndrome Z is also linked to intracoronary stenosis related to changes in cardiac morphology²⁸ and is associated with left ventricular hypertrophy and diastolic dysfunction.²⁹

OSA and hypertension

Hypertension is one of the conditions encompassed in metabolic syndrome. Several studies report increased risk and incidence of hypertension in patients with OSA. In a community-based study of 6,123 individuals age 40 and older, sleep-disordered breathing was associated with hypertension, and the odds ratio of hypertension was greater in individuals with more severe sleep apnea.³⁰ Similarly, a landmark prospective, population-based study of 709 individuals over 4 years reported a dose-response relationship between patients with OSA and newly diagnosed hypertension independent of confounding factors.³¹ Patients with moderate to severe OSA had an odds ratio of 2.89 of developing hypertension after adjusting for confounding variables.

A study of 1,889 individuals followed for 12 years found a dose-response relationship based on OSA severity for developing hypertension.³² This study also assessed the incidence of hypertension based on CPAP use. Patients with poor adherence to CPAP use had an 80% increased incidence of hypertension, whereas patients adhering to CPAP use had a 30% decrease in the incidence of hypertension.

Resistant hypertension (ie, uncontrolled hypertension despite use of 3 or more antihypertensive and diuretic medications) has been shown to be highly prevalent (85%) in patients with severe OSA.³³ An analysis of patients at increased risk of cardiovascular disease and untreated severe OSA was associated with a 4 times higher risk of elevated blood pressure despite intensive medical therapy.³⁴

Mechanisms implicated in altering metabolic regulation in OSA include intermittent hypoxia, sleep fragmentation and glucose homeostasis, and obesity. Intermittent hypoxia from OSA results in sympathetic nervous system activation that affects the pancreas, skeletal muscle, liver, and fat cells resulting in altered insulin secretion, lipid-bile synthesis, glucose metabolism, and lipoprotein metabolism.³⁵

Sleep fragmentation is a cardinal feature of OSA and the resulting suppression of sleep may alter insulin sensitivity. Studies have implicated disruptions to slow-wave sleep specifically, as well as disruption of any stage of sleep in reduced insulin sensitivity.^35,36 In addition to decreased insulin sensitivity, sleep fragmentation also increases morning cortisol levels and increases sympathetic nervous system activation.³⁷

Obesity and OSA share a pathway imparting increased cardiometabolic risk.³⁸ Fat tissue causes higher systemic inflammation and inflammatory markers. A recent report describes a bidirectional relationship between metabolic syndrome and OSA.³⁹ While OSA increases the risk for metabolic syndrome, metabolic syndrome by virtue of body mass index with changes in mechanical load and narrow airway and physiology can predispose for OSA.

Effect of treatment for OSA on metabolic syndrome

Several studies have evaluated the effect of CPAP treatment for OSA on metabolic syndrome overall, as well as the specific conditions that comprise metabolic syndrome. In evaluating CPAP use and metabolic syndrome overall, studies have found a reduced prevalence of metabolic syndrome,^40,41 CPAP benefit only in complying patients,⁴² and a reduction in oxidative stress with a single-night use of CPAP.⁴³

With respect to insulin sensitivity, a study of 40 men with moderate OSA using CPAP therapy (mean use 5 hours) reported an increase in the insulin sensitivity index after 2 days, and a further increase after 3 months.⁴⁴ Another study found no improvement in insulin resistance in severe OSA.⁴⁵ A meta-analysis reported improved insulin resistance with CPAP,⁴⁶ although a recent meta-analysis assessing hemoglobin A_1c level, fasting insulin level, and fasting glucose did not show improvement in these parameters. Large-scale clinical trials with longer treatment duration and better CPAP compliance are warranted.⁴⁷

Weight loss has been shown to reduce the AHI and other parameters related to sleep apnea such as oxygen desaturation index in patients with obesity and diabetes.⁵⁹ Weight loss combined with CPAP compared with CPAP or weight loss alone showed an incremental benefit in improving glucose parameters, triglycerides, and possibly systolic blood pressure and triglycerides.⁶⁰

Data suggest that OSA is linked with cognitive impairment, may advance cognitive decline, and is a bidirectional relationship. Women with OSA were reportedly more likely to develop mild cognitive impairment compared with women without OSA.⁶¹ An elevated oxygen desaturation index and a high percentage of time spent with hypoxia was associated with increased risk of developing mild cognitive impairment and dementia.

OSA was found to be an independent risk factor for cerebral white matter changes in middle-age and older individuals. Moderate to severe OSA imparted a 2 times higher risk of cerebral white matter changes compared with individuals without OSA.⁶² Another study of 20 patients with severe OSA compared with 40 healthy volunteers found diffusion imaging consistent with impaired fibrin integrity in those with OSA, indicative of white matter microstructure damage, and the impairment was associated with increased disease severity and higher systemic inflammation.⁶³

Individuals with hypoxia for a high percentage of time during sleep had a 4 times higher odds of cerebral microinfarcts.⁶⁴ Cognitive scores decreased less in men. Men typically have more time in slow-wave sleep, suggesting that slow-wave sleep may be protective against cognitive decline. Mild cognitive impairment and Alzheimer disease were found more likely to develop and occur at an earlier age in individuals with sleep-disordered breathing compared with individuals without sleep-disordered breathing.⁶⁵

OSA was also associated with increased serum amyloid beta levels in a study of 45 cognitively normal patients with OSA compared with 49 age- and sex-matched control patients. Increased amyloid beta levels correlated with increasing severity of sleep apnea as measured by the AHI.⁶⁶

Mechanism linking OSA and cognition

One possible mechanism linking sleep quality and cognitive impairment or Alzheimer disease is the role of unfragmented sleep in attenuating the apolipo­protein E e4 allele on the incidence of Alzheimer disease.⁶⁷ Beta amyloid is released during synaptic activity. Neuronal and synaptic activity decreases during sleep, and disrupted sleep could increase beta amyloid release.⁶⁸ Sleep has been found to enhance the clearance of beta amyloid peptide from the brain interstitial fluid in a mice model.⁶⁹

Recent data point toward the bidirectional relationship between the sleep and Alzheimer disease in that excessive and prolonged neuronal activity in the absence of appropriately structured sleep may be the reason for both Alzheimer disease and OSA.^70,71

Effect of treatment for OSA on cognition

White matter integrity in 15 patients with OSA before and after treatment with CPAP was compared with 15 matched controls. Over 12 months, there was a nearly complete reversal of white matter abnormalities in patients on CPAP therapy.⁷² Improvement in memory, attention, and executive function paralleled the changes in white matter after the treatment.

CONCLUSION

OSA is a serious condition with far-reaching consequences associated with impaired quality of life, depressive symptoms, drowsy driving, metabolic disease, and cognitive decline. Treatment of OSA improves many of these health consequences, emphasizing the need for OSA screening. Large randomized studies are needed to assess the efficacy of CPAP on metabolic outcomes, including insulin sensitivity and glucose tolerance, in reducing disease burden. Study of the endophenotypes of patients with OSA is needed to define and target the mechanisms of OSA-induced adverse health outcomes and perhaps lead to personalized care for patients with OSA.

Obstructive sleep apnea (OSA) is a serious condition that impacts quality of life and causes drowsy driving and depression. Research also reveals an interrelationship between OSA and metabolic disease and an association between OSA and cognitive impairment.

The diagnostic criteria of OSA are based on the number of apneic or hypopneic episodes per hour of sleep, called the apnea–hypopnea index (AHI) as recorded during sleep testing. Diagnosis of OSA is warranted if the AHI is 15 or more per hour or if the AHI is 5 or more per hour with 1 or more of the following features: sleepiness; nonrestorative sleep; fatigue or insomnia; waking up with breath-holding spells, gasping, or choking; snoring or breathing interruptions; or a coexisting diagnosis of hypertension, mood disorder, cognitive dysfunction, coronary artery disease, stroke, congestive heart failure, atrial fibrillation, or type II diabetes.¹

Many patients with an AHI less than 15 may also have OSA, given the number of coexisting medical conditions included in the OSA diagnostic criteria. Heart conditions such as coronary artery disease, atrial fibrillation, and congestive heart failure encompassed in the OSA diagnostic criteria have increased awareness of the link between OSA and heart health. Less well-known, and the subject of this review, are the negative consequences of OSA, particularly poor quality of life, drowsy driving, depression, metabolic disease, and cognitive impairment.

QUALITY OF LIFE

Reduced quality of life is the most fundamental patient-reported outcome of OSA. OSA is associated with excessive daytime sleepiness, inattention, and fatigue, which increase the risk of accidents and medical disability. These quality-of-life impairments are often the main reason patients seek medical care for sleep disorders.² Improved quality of life is a central goal of OSA treatment and is the best indicator of the effectiveness of treatment.³ Sleep health and its effect on quality of life is an area of focus of Healthy People 2020 (healthypeople.gov).

The American Academy of Sleep Medicine identified quality of life, along with detection of disease and cardiovascular consequences, as an outcome measure for assessing the quality of care for adults with OSA.² The assessment of quality of life for patients with OSA is a 4-part process: use evidence-based therapy, monitor the therapy, assess symptoms with a validated tool such as Epworth Sleepiness Scale, and assess the incidence of motor vehicle accidents. Information from these 4 processes can inform changes in a patient’s quality of life.

Treatment for OSA has been shown to improve quality of life. A study of 2,027 patients with OSA evaluated therapy adherence relative to mean Functional Outcomes of Sleep Questionnaire and European Quality of Life-5D scores.⁴ In patients with the most impaired quality of life, those adherent to positive airway pressure (PAP) therapy had improved quality of life as measured by these scores.

With respect to sleepiness, a systematic review of continuous PAP (CPAP) in patients with OSA found a 2.7-point reduction (mean difference; 95% confidence interval 3.45–1.96) in the Epworth Sleepiness Scale in patients using CPAP compared with the control group.⁵ Treatment of OSA improves patient quality of life and symptoms such as sleepiness.

DROWSY DRIVING

Drowsy driving by people with OSA can lead to motor vehicle accidents, which result in economic and health burdens.^6,7 National Center for Statistics and Analysis data reveal that of 6 million motor vehicle accidents (5-year average, 2005–2009), 1.4% involve drowsy driving and 2.5% of fatal crashes involve drowsy driving.⁸ Among noncommercial drivers, untreated OSA increases the risk of motor vehicle accidents 3- to 13-fold.⁹ The odds ratio of traffic accidents in drivers with untreated OSA is 6 times greater than in the general population.⁷

In a study of men and women in the general population (N = 913), individuals with moderate to severe OSA (AHI > 15) were more likely to have multiple motor vehicle accidents in the course of 5 years (odds ratio = 7.3) compared with those with no sleep-disordered breathing.¹⁰ The association between OSA and motor vehicle accidents is independent of sleepiness, and drivers with OSA may not perceive performance impairment.

There are 2 main reasons OSA increases the risk and incidence of motor vehicle accidents. OSA causes changes in attention and vigilance resulting from sleep deprivation and fragmentation. OSA also affects global cognition function, which may be due to intermittent hypoxia attributable to OSA.²

Treatment for OSA is effective in reducing the incidence of motor vehicle accidents. One study found the risk of motor vehicle accidents was eliminated with the use of CPAP treatment in patients with OSA.¹¹ A recent study of nearly 2,000 patients with OSA found a reduction in self-reported near-accidents from 14% before PAP therapy to 5.3% after starting PAP therapy.¹²

Estimates of the prevalence of depression in patients with OSA range from 5% to 63%.^13,14 One year after patients were diagnosed with OSA, the incidence of depression per 1,000 person-years was 18% compared with 8% in a group without OSA.¹⁴ Women with OSA reportedly have a higher risk of depression (adjusted hazard ratio [HR] 2.7) than men (HR 1.81) at 1-year follow-up.¹⁴ In the same study, with respect to age, there was no significant relationship noted between OSA and patients over age 64.

A one-level increase in the severity of OSA (ie, from minimal to mild) is associated with a nearly twofold increase in the adjusted odds for depression.¹⁵ On the other hand, studies have also found that patients on antidepressants may have an increased risk of OSA.¹⁶

Several potential mechanisms have been proposed to explain the link between depression and OSA.¹³ Poor-quality sleep, frequent arousal, and fragmentation of sleep in OSA may lead to frontal lobe emotional modulation changes. Intermittent hypoxia in OSA may result in neuronal injury and disruption of noradrenergic and dopaminergic pathways. Pro-inflammatory substances such as interleukin 6 and interleukin 1 are increased in OSA and depression and are mediators between both conditions. Neurotransmitters may be affected by a disrupted sleep-wake cycle. And serotonin, which may be impeded in depression, could influence the upper-airway dilator motor neurons.

Treatment of OSA improves symptoms of depression as measured by the Patient Health Questionnaire (PHQ-9). After 3 months of compliance with CPAP therapy, mean PHQ-9 scores decreased from 11.3 to 2.7 in a study of 228 patients with OSA.¹⁷ A study of 1,981 patients with sleep-disordered breathing found improved PHQ-9 scores in patients compliant with CPAP therapy and a greater improvement in patients with a baseline PHQ-9 higher than 10 (moderate severity).¹⁸

METABOLIC SYNDROME

OSA is associated with metabolic disorders, including metabolic syndrome, though the causality between these 2 conditions is yet to be illuminated. Metabolic syndrome is a term used when an individual has 3 or more of the following features or conditions:

• Waist circumference greater than 40 inches (men), greater than 35 inches (women)
• Triglycerides 150 mg/dL or greater or treatment for hypertriglyceridemia
• High-density lipoprotein cholesterol less than 40 mg/dL (men), less than 50 mg/dL (women), or treatment for cholesterol
• Blood pressure 130/85 mm Hg or greater, or treatment for hypertension
• Fasting blood glucose 100 mg/dL or greater, or treatment for hyperglycemia.¹⁹

Metabolic syndrome increases an individual’s risk of diabetes and cardiovascular disease and overall mortality. Like OSA, the prevalence of metabolic syndrome increases with age in both men and women.^20,21 The risk of metabolic syndrome is greater with more severe OSA. The Wisconsin Sleep Cohort (N = 546) reported an odds ratio for having metabolic syndrome of 2.5 for patients with mild OSA and 2.2 for patients with moderate or severe OSA.²² A meta-analysis also found a 2.4 times higher odds of metabolic syndrome in patients with mild OSA, but a 3.5 times higher odds of metabolic syndrome in patients with moderate to severe OSA compared with the control group.²³

Patients with both OSA and metabolic syndrome are said to have syndrome Z²⁴ and are at increased risk of cardiovascular morbidity and mortality.²⁵ Syndrome Z imparts a higher risk of atherogenic burden and prevalence of atheroma compared with patients with either condition alone.²⁶ In comparing patients with metabolic syndrome with and without OSA, those with OSA had increased atherosclerotic burden as measured by intima-media thickness and carotid femoral pulse-wave velocity.²⁷ Syndrome Z is also linked to intracoronary stenosis related to changes in cardiac morphology²⁸ and is associated with left ventricular hypertrophy and diastolic dysfunction.²⁹

OSA and hypertension

Hypertension is one of the conditions encompassed in metabolic syndrome. Several studies report increased risk and incidence of hypertension in patients with OSA. In a community-based study of 6,123 individuals age 40 and older, sleep-disordered breathing was associated with hypertension, and the odds ratio of hypertension was greater in individuals with more severe sleep apnea.³⁰ Similarly, a landmark prospective, population-based study of 709 individuals over 4 years reported a dose-response relationship between patients with OSA and newly diagnosed hypertension independent of confounding factors.³¹ Patients with moderate to severe OSA had an odds ratio of 2.89 of developing hypertension after adjusting for confounding variables.

A study of 1,889 individuals followed for 12 years found a dose-response relationship based on OSA severity for developing hypertension.³² This study also assessed the incidence of hypertension based on CPAP use. Patients with poor adherence to CPAP use had an 80% increased incidence of hypertension, whereas patients adhering to CPAP use had a 30% decrease in the incidence of hypertension.

Resistant hypertension (ie, uncontrolled hypertension despite use of 3 or more antihypertensive and diuretic medications) has been shown to be highly prevalent (85%) in patients with severe OSA.³³ An analysis of patients at increased risk of cardiovascular disease and untreated severe OSA was associated with a 4 times higher risk of elevated blood pressure despite intensive medical therapy.³⁴

Mechanisms implicated in altering metabolic regulation in OSA include intermittent hypoxia, sleep fragmentation and glucose homeostasis, and obesity. Intermittent hypoxia from OSA results in sympathetic nervous system activation that affects the pancreas, skeletal muscle, liver, and fat cells resulting in altered insulin secretion, lipid-bile synthesis, glucose metabolism, and lipoprotein metabolism.³⁵

Sleep fragmentation is a cardinal feature of OSA and the resulting suppression of sleep may alter insulin sensitivity. Studies have implicated disruptions to slow-wave sleep specifically, as well as disruption of any stage of sleep in reduced insulin sensitivity.^35,36 In addition to decreased insulin sensitivity, sleep fragmentation also increases morning cortisol levels and increases sympathetic nervous system activation.³⁷

Obesity and OSA share a pathway imparting increased cardiometabolic risk.³⁸ Fat tissue causes higher systemic inflammation and inflammatory markers. A recent report describes a bidirectional relationship between metabolic syndrome and OSA.³⁹ While OSA increases the risk for metabolic syndrome, metabolic syndrome by virtue of body mass index with changes in mechanical load and narrow airway and physiology can predispose for OSA.

Effect of treatment for OSA on metabolic syndrome

Several studies have evaluated the effect of CPAP treatment for OSA on metabolic syndrome overall, as well as the specific conditions that comprise metabolic syndrome. In evaluating CPAP use and metabolic syndrome overall, studies have found a reduced prevalence of metabolic syndrome,^40,41 CPAP benefit only in complying patients,⁴² and a reduction in oxidative stress with a single-night use of CPAP.⁴³

With respect to insulin sensitivity, a study of 40 men with moderate OSA using CPAP therapy (mean use 5 hours) reported an increase in the insulin sensitivity index after 2 days, and a further increase after 3 months.⁴⁴ Another study found no improvement in insulin resistance in severe OSA.⁴⁵ A meta-analysis reported improved insulin resistance with CPAP,⁴⁶ although a recent meta-analysis assessing hemoglobin A_1c level, fasting insulin level, and fasting glucose did not show improvement in these parameters. Large-scale clinical trials with longer treatment duration and better CPAP compliance are warranted.⁴⁷

Weight loss has been shown to reduce the AHI and other parameters related to sleep apnea such as oxygen desaturation index in patients with obesity and diabetes.⁵⁹ Weight loss combined with CPAP compared with CPAP or weight loss alone showed an incremental benefit in improving glucose parameters, triglycerides, and possibly systolic blood pressure and triglycerides.⁶⁰

Data suggest that OSA is linked with cognitive impairment, may advance cognitive decline, and is a bidirectional relationship. Women with OSA were reportedly more likely to develop mild cognitive impairment compared with women without OSA.⁶¹ An elevated oxygen desaturation index and a high percentage of time spent with hypoxia was associated with increased risk of developing mild cognitive impairment and dementia.

OSA was found to be an independent risk factor for cerebral white matter changes in middle-age and older individuals. Moderate to severe OSA imparted a 2 times higher risk of cerebral white matter changes compared with individuals without OSA.⁶² Another study of 20 patients with severe OSA compared with 40 healthy volunteers found diffusion imaging consistent with impaired fibrin integrity in those with OSA, indicative of white matter microstructure damage, and the impairment was associated with increased disease severity and higher systemic inflammation.⁶³

Individuals with hypoxia for a high percentage of time during sleep had a 4 times higher odds of cerebral microinfarcts.⁶⁴ Cognitive scores decreased less in men. Men typically have more time in slow-wave sleep, suggesting that slow-wave sleep may be protective against cognitive decline. Mild cognitive impairment and Alzheimer disease were found more likely to develop and occur at an earlier age in individuals with sleep-disordered breathing compared with individuals without sleep-disordered breathing.⁶⁵

OSA was also associated with increased serum amyloid beta levels in a study of 45 cognitively normal patients with OSA compared with 49 age- and sex-matched control patients. Increased amyloid beta levels correlated with increasing severity of sleep apnea as measured by the AHI.⁶⁶

Mechanism linking OSA and cognition

One possible mechanism linking sleep quality and cognitive impairment or Alzheimer disease is the role of unfragmented sleep in attenuating the apolipo­protein E e4 allele on the incidence of Alzheimer disease.⁶⁷ Beta amyloid is released during synaptic activity. Neuronal and synaptic activity decreases during sleep, and disrupted sleep could increase beta amyloid release.⁶⁸ Sleep has been found to enhance the clearance of beta amyloid peptide from the brain interstitial fluid in a mice model.⁶⁹

Recent data point toward the bidirectional relationship between the sleep and Alzheimer disease in that excessive and prolonged neuronal activity in the absence of appropriately structured sleep may be the reason for both Alzheimer disease and OSA.^70,71

Effect of treatment for OSA on cognition

White matter integrity in 15 patients with OSA before and after treatment with CPAP was compared with 15 matched controls. Over 12 months, there was a nearly complete reversal of white matter abnormalities in patients on CPAP therapy.⁷² Improvement in memory, attention, and executive function paralleled the changes in white matter after the treatment.

CONCLUSION

OSA is a serious condition with far-reaching consequences associated with impaired quality of life, depressive symptoms, drowsy driving, metabolic disease, and cognitive decline. Treatment of OSA improves many of these health consequences, emphasizing the need for OSA screening. Large randomized studies are needed to assess the efficacy of CPAP on metabolic outcomes, including insulin sensitivity and glucose tolerance, in reducing disease burden. Study of the endophenotypes of patients with OSA is needed to define and target the mechanisms of OSA-induced adverse health outcomes and perhaps lead to personalized care for patients with OSA.

Obstructive sleep apnea (OSA) is a serious condition that impacts quality of life and causes drowsy driving and depression. Research also reveals an interrelationship between OSA and metabolic disease and an association between OSA and cognitive impairment.

The diagnostic criteria of OSA are based on the number of apneic or hypopneic episodes per hour of sleep, called the apnea–hypopnea index (AHI) as recorded during sleep testing. Diagnosis of OSA is warranted if the AHI is 15 or more per hour or if the AHI is 5 or more per hour with 1 or more of the following features: sleepiness; nonrestorative sleep; fatigue or insomnia; waking up with breath-holding spells, gasping, or choking; snoring or breathing interruptions; or a coexisting diagnosis of hypertension, mood disorder, cognitive dysfunction, coronary artery disease, stroke, congestive heart failure, atrial fibrillation, or type II diabetes.¹

Many patients with an AHI less than 15 may also have OSA, given the number of coexisting medical conditions included in the OSA diagnostic criteria. Heart conditions such as coronary artery disease, atrial fibrillation, and congestive heart failure encompassed in the OSA diagnostic criteria have increased awareness of the link between OSA and heart health. Less well-known, and the subject of this review, are the negative consequences of OSA, particularly poor quality of life, drowsy driving, depression, metabolic disease, and cognitive impairment.

QUALITY OF LIFE

Reduced quality of life is the most fundamental patient-reported outcome of OSA. OSA is associated with excessive daytime sleepiness, inattention, and fatigue, which increase the risk of accidents and medical disability. These quality-of-life impairments are often the main reason patients seek medical care for sleep disorders.² Improved quality of life is a central goal of OSA treatment and is the best indicator of the effectiveness of treatment.³ Sleep health and its effect on quality of life is an area of focus of Healthy People 2020 (healthypeople.gov).

The American Academy of Sleep Medicine identified quality of life, along with detection of disease and cardiovascular consequences, as an outcome measure for assessing the quality of care for adults with OSA.² The assessment of quality of life for patients with OSA is a 4-part process: use evidence-based therapy, monitor the therapy, assess symptoms with a validated tool such as Epworth Sleepiness Scale, and assess the incidence of motor vehicle accidents. Information from these 4 processes can inform changes in a patient’s quality of life.

Treatment for OSA has been shown to improve quality of life. A study of 2,027 patients with OSA evaluated therapy adherence relative to mean Functional Outcomes of Sleep Questionnaire and European Quality of Life-5D scores.⁴ In patients with the most impaired quality of life, those adherent to positive airway pressure (PAP) therapy had improved quality of life as measured by these scores.

With respect to sleepiness, a systematic review of continuous PAP (CPAP) in patients with OSA found a 2.7-point reduction (mean difference; 95% confidence interval 3.45–1.96) in the Epworth Sleepiness Scale in patients using CPAP compared with the control group.⁵ Treatment of OSA improves patient quality of life and symptoms such as sleepiness.

DROWSY DRIVING

Drowsy driving by people with OSA can lead to motor vehicle accidents, which result in economic and health burdens.^6,7 National Center for Statistics and Analysis data reveal that of 6 million motor vehicle accidents (5-year average, 2005–2009), 1.4% involve drowsy driving and 2.5% of fatal crashes involve drowsy driving.⁸ Among noncommercial drivers, untreated OSA increases the risk of motor vehicle accidents 3- to 13-fold.⁹ The odds ratio of traffic accidents in drivers with untreated OSA is 6 times greater than in the general population.⁷

In a study of men and women in the general population (N = 913), individuals with moderate to severe OSA (AHI > 15) were more likely to have multiple motor vehicle accidents in the course of 5 years (odds ratio = 7.3) compared with those with no sleep-disordered breathing.¹⁰ The association between OSA and motor vehicle accidents is independent of sleepiness, and drivers with OSA may not perceive performance impairment.

There are 2 main reasons OSA increases the risk and incidence of motor vehicle accidents. OSA causes changes in attention and vigilance resulting from sleep deprivation and fragmentation. OSA also affects global cognition function, which may be due to intermittent hypoxia attributable to OSA.²

Treatment for OSA is effective in reducing the incidence of motor vehicle accidents. One study found the risk of motor vehicle accidents was eliminated with the use of CPAP treatment in patients with OSA.¹¹ A recent study of nearly 2,000 patients with OSA found a reduction in self-reported near-accidents from 14% before PAP therapy to 5.3% after starting PAP therapy.¹²

Estimates of the prevalence of depression in patients with OSA range from 5% to 63%.^13,14 One year after patients were diagnosed with OSA, the incidence of depression per 1,000 person-years was 18% compared with 8% in a group without OSA.¹⁴ Women with OSA reportedly have a higher risk of depression (adjusted hazard ratio [HR] 2.7) than men (HR 1.81) at 1-year follow-up.¹⁴ In the same study, with respect to age, there was no significant relationship noted between OSA and patients over age 64.

A one-level increase in the severity of OSA (ie, from minimal to mild) is associated with a nearly twofold increase in the adjusted odds for depression.¹⁵ On the other hand, studies have also found that patients on antidepressants may have an increased risk of OSA.¹⁶

Several potential mechanisms have been proposed to explain the link between depression and OSA.¹³ Poor-quality sleep, frequent arousal, and fragmentation of sleep in OSA may lead to frontal lobe emotional modulation changes. Intermittent hypoxia in OSA may result in neuronal injury and disruption of noradrenergic and dopaminergic pathways. Pro-inflammatory substances such as interleukin 6 and interleukin 1 are increased in OSA and depression and are mediators between both conditions. Neurotransmitters may be affected by a disrupted sleep-wake cycle. And serotonin, which may be impeded in depression, could influence the upper-airway dilator motor neurons.

Treatment of OSA improves symptoms of depression as measured by the Patient Health Questionnaire (PHQ-9). After 3 months of compliance with CPAP therapy, mean PHQ-9 scores decreased from 11.3 to 2.7 in a study of 228 patients with OSA.¹⁷ A study of 1,981 patients with sleep-disordered breathing found improved PHQ-9 scores in patients compliant with CPAP therapy and a greater improvement in patients with a baseline PHQ-9 higher than 10 (moderate severity).¹⁸

METABOLIC SYNDROME

OSA is associated with metabolic disorders, including metabolic syndrome, though the causality between these 2 conditions is yet to be illuminated. Metabolic syndrome is a term used when an individual has 3 or more of the following features or conditions:

• Waist circumference greater than 40 inches (men), greater than 35 inches (women)
• Triglycerides 150 mg/dL or greater or treatment for hypertriglyceridemia
• High-density lipoprotein cholesterol less than 40 mg/dL (men), less than 50 mg/dL (women), or treatment for cholesterol
• Blood pressure 130/85 mm Hg or greater, or treatment for hypertension
• Fasting blood glucose 100 mg/dL or greater, or treatment for hyperglycemia.¹⁹

Metabolic syndrome increases an individual’s risk of diabetes and cardiovascular disease and overall mortality. Like OSA, the prevalence of metabolic syndrome increases with age in both men and women.^20,21 The risk of metabolic syndrome is greater with more severe OSA. The Wisconsin Sleep Cohort (N = 546) reported an odds ratio for having metabolic syndrome of 2.5 for patients with mild OSA and 2.2 for patients with moderate or severe OSA.²² A meta-analysis also found a 2.4 times higher odds of metabolic syndrome in patients with mild OSA, but a 3.5 times higher odds of metabolic syndrome in patients with moderate to severe OSA compared with the control group.²³

Patients with both OSA and metabolic syndrome are said to have syndrome Z²⁴ and are at increased risk of cardiovascular morbidity and mortality.²⁵ Syndrome Z imparts a higher risk of atherogenic burden and prevalence of atheroma compared with patients with either condition alone.²⁶ In comparing patients with metabolic syndrome with and without OSA, those with OSA had increased atherosclerotic burden as measured by intima-media thickness and carotid femoral pulse-wave velocity.²⁷ Syndrome Z is also linked to intracoronary stenosis related to changes in cardiac morphology²⁸ and is associated with left ventricular hypertrophy and diastolic dysfunction.²⁹

OSA and hypertension

Hypertension is one of the conditions encompassed in metabolic syndrome. Several studies report increased risk and incidence of hypertension in patients with OSA. In a community-based study of 6,123 individuals age 40 and older, sleep-disordered breathing was associated with hypertension, and the odds ratio of hypertension was greater in individuals with more severe sleep apnea.³⁰ Similarly, a landmark prospective, population-based study of 709 individuals over 4 years reported a dose-response relationship between patients with OSA and newly diagnosed hypertension independent of confounding factors.³¹ Patients with moderate to severe OSA had an odds ratio of 2.89 of developing hypertension after adjusting for confounding variables.

A study of 1,889 individuals followed for 12 years found a dose-response relationship based on OSA severity for developing hypertension.³² This study also assessed the incidence of hypertension based on CPAP use. Patients with poor adherence to CPAP use had an 80% increased incidence of hypertension, whereas patients adhering to CPAP use had a 30% decrease in the incidence of hypertension.

Resistant hypertension (ie, uncontrolled hypertension despite use of 3 or more antihypertensive and diuretic medications) has been shown to be highly prevalent (85%) in patients with severe OSA.³³ An analysis of patients at increased risk of cardiovascular disease and untreated severe OSA was associated with a 4 times higher risk of elevated blood pressure despite intensive medical therapy.³⁴

Mechanisms implicated in altering metabolic regulation in OSA include intermittent hypoxia, sleep fragmentation and glucose homeostasis, and obesity. Intermittent hypoxia from OSA results in sympathetic nervous system activation that affects the pancreas, skeletal muscle, liver, and fat cells resulting in altered insulin secretion, lipid-bile synthesis, glucose metabolism, and lipoprotein metabolism.³⁵

Sleep fragmentation is a cardinal feature of OSA and the resulting suppression of sleep may alter insulin sensitivity. Studies have implicated disruptions to slow-wave sleep specifically, as well as disruption of any stage of sleep in reduced insulin sensitivity.^35,36 In addition to decreased insulin sensitivity, sleep fragmentation also increases morning cortisol levels and increases sympathetic nervous system activation.³⁷

Obesity and OSA share a pathway imparting increased cardiometabolic risk.³⁸ Fat tissue causes higher systemic inflammation and inflammatory markers. A recent report describes a bidirectional relationship between metabolic syndrome and OSA.³⁹ While OSA increases the risk for metabolic syndrome, metabolic syndrome by virtue of body mass index with changes in mechanical load and narrow airway and physiology can predispose for OSA.

Effect of treatment for OSA on metabolic syndrome

Several studies have evaluated the effect of CPAP treatment for OSA on metabolic syndrome overall, as well as the specific conditions that comprise metabolic syndrome. In evaluating CPAP use and metabolic syndrome overall, studies have found a reduced prevalence of metabolic syndrome,^40,41 CPAP benefit only in complying patients,⁴² and a reduction in oxidative stress with a single-night use of CPAP.⁴³

With respect to insulin sensitivity, a study of 40 men with moderate OSA using CPAP therapy (mean use 5 hours) reported an increase in the insulin sensitivity index after 2 days, and a further increase after 3 months.⁴⁴ Another study found no improvement in insulin resistance in severe OSA.⁴⁵ A meta-analysis reported improved insulin resistance with CPAP,⁴⁶ although a recent meta-analysis assessing hemoglobin A_1c level, fasting insulin level, and fasting glucose did not show improvement in these parameters. Large-scale clinical trials with longer treatment duration and better CPAP compliance are warranted.⁴⁷

Weight loss has been shown to reduce the AHI and other parameters related to sleep apnea such as oxygen desaturation index in patients with obesity and diabetes.⁵⁹ Weight loss combined with CPAP compared with CPAP or weight loss alone showed an incremental benefit in improving glucose parameters, triglycerides, and possibly systolic blood pressure and triglycerides.⁶⁰

Data suggest that OSA is linked with cognitive impairment, may advance cognitive decline, and is a bidirectional relationship. Women with OSA were reportedly more likely to develop mild cognitive impairment compared with women without OSA.⁶¹ An elevated oxygen desaturation index and a high percentage of time spent with hypoxia was associated with increased risk of developing mild cognitive impairment and dementia.

OSA was found to be an independent risk factor for cerebral white matter changes in middle-age and older individuals. Moderate to severe OSA imparted a 2 times higher risk of cerebral white matter changes compared with individuals without OSA.⁶² Another study of 20 patients with severe OSA compared with 40 healthy volunteers found diffusion imaging consistent with impaired fibrin integrity in those with OSA, indicative of white matter microstructure damage, and the impairment was associated with increased disease severity and higher systemic inflammation.⁶³

Individuals with hypoxia for a high percentage of time during sleep had a 4 times higher odds of cerebral microinfarcts.⁶⁴ Cognitive scores decreased less in men. Men typically have more time in slow-wave sleep, suggesting that slow-wave sleep may be protective against cognitive decline. Mild cognitive impairment and Alzheimer disease were found more likely to develop and occur at an earlier age in individuals with sleep-disordered breathing compared with individuals without sleep-disordered breathing.⁶⁵

OSA was also associated with increased serum amyloid beta levels in a study of 45 cognitively normal patients with OSA compared with 49 age- and sex-matched control patients. Increased amyloid beta levels correlated with increasing severity of sleep apnea as measured by the AHI.⁶⁶

Mechanism linking OSA and cognition

One possible mechanism linking sleep quality and cognitive impairment or Alzheimer disease is the role of unfragmented sleep in attenuating the apolipo­protein E e4 allele on the incidence of Alzheimer disease.⁶⁷ Beta amyloid is released during synaptic activity. Neuronal and synaptic activity decreases during sleep, and disrupted sleep could increase beta amyloid release.⁶⁸ Sleep has been found to enhance the clearance of beta amyloid peptide from the brain interstitial fluid in a mice model.⁶⁹

Recent data point toward the bidirectional relationship between the sleep and Alzheimer disease in that excessive and prolonged neuronal activity in the absence of appropriately structured sleep may be the reason for both Alzheimer disease and OSA.^70,71

Effect of treatment for OSA on cognition

White matter integrity in 15 patients with OSA before and after treatment with CPAP was compared with 15 matched controls. Over 12 months, there was a nearly complete reversal of white matter abnormalities in patients on CPAP therapy.⁷² Improvement in memory, attention, and executive function paralleled the changes in white matter after the treatment.

CONCLUSION

OSA is a serious condition with far-reaching consequences associated with impaired quality of life, depressive symptoms, drowsy driving, metabolic disease, and cognitive decline. Treatment of OSA improves many of these health consequences, emphasizing the need for OSA screening. Large randomized studies are needed to assess the efficacy of CPAP on metabolic outcomes, including insulin sensitivity and glucose tolerance, in reducing disease burden. Study of the endophenotypes of patients with OSA is needed to define and target the mechanisms of OSA-induced adverse health outcomes and perhaps lead to personalized care for patients with OSA.

EFFICACY OF PAP THERAPY

The American Academy of Sleep Medicine practice guidelines for PAP are based on 342 articles, most rated as evidence levels I and II, concluding that CPAP is superior to conservative treatment to:

• Eliminate respiratory disturbances
• Reduce the apnea–hypopnea index
• Decrease the arousal index on electroencephalogram
• Increase in the total amount of slow-wave or N3 sleep
• Reduce daytime sleepiness.²

These practice parameters are based on evidence of improved daytime sleepiness and reduced incidence of cardiovascular events in patients with moderate to severe obstructive sleep apnea (OSA) treated with PAP. The evidence is less clear for neurocognitive markers and cardiovascular events in the treatment of patients with mild sleep apnea.

Sleepiness

A study evaluated sleepiness outcomes in 149 patients with severe sleep apnea with an average apnea–hypopnea index of 69 relative to the duration of nightly CPAP use. Sleepiness was measured using the Functional Outcomes of Sleep Questionnaire, Epworth Sleepiness Scale, and Multiple Sleep Latency Test. Results suggest that a greater percentage of patients had improved daytime sleepiness as the total hours of sleep using CPAP increased.³

The Apnea Positive Pressure Long-term Efficacy Study (APPLES) was a 6-month, multicenter, randomized study of neurocognitive function in patients with OSA (N = 1,098).⁴ Subjective sleepiness as measured by the Epworth Sleepiness Scale showed statistically significant improvement at 2 and 6 months for patients with moderate to severe OSA using CPAP. Objective sleepiness as measured by the Maintenance of Wakefulness Test showed statistically significant improvement (ie, improved daytime alertness) at 2 and 6 months for patients with severe OSA using CPAP.

Neurocognitive function

APPLES also tested for attention and psycho­motor function as well as verbal learning and memory, though no statistically significant improvements were found in these parameters.⁴ Executive function and frontal lobe function showed transient improvement at 2 months in patients with severe sleep apnea using CPAP, but the improvement was not statistically significant at 6 months.

Cardiovascular outcomes

Hypertension and cardiovascular disease. Use of CPAP therapy reduces blood pressure in individuals with hypertension. A study of 32 patients who had a baseline polysomnography with 19 hours of continuous mean arterial blood pressure monitoring were treated with therapeutic CPAP (n = 16) or subtherapeutic CPAP (n = 16).⁵ Therapeutic treatment with CPAP for patients with moderate to severe OSA resulted in statistically significant reductions in mean arterial pressure for both systolic and diastolic pressures. The blood pressure reductions achieved are estimated to reduce coronary artery diseases by 37% and stroke by 56%.⁵

The risk of cardiovascular events in men with severe sleep apnea is high but mitigated by the use of CPAP. In a cohort of 1,651 men, untreated severe sleep apnea resulted in a threefold increase in the rate of cardiovascular events per 1,000 patient-years compared with 4 other groups: a control group, men who snore, men with untreated mild to moderate sleep apnea, and men with OSA using CPAP.⁶ However, when men with severe sleep apnea use CPAP, the risk of cardiovascular events is reduced to the rate in men who snore.

Atrial fibrillation. In patients with atrial fibrillation treated with direct-current cardioversion-
defibrillation, the recurrence of atrial fibrillation at 12 months was greater in patients with untreated OSA (82%) compared with a control group (53%) and patients treated for OSA (42%).⁷

Heart failure. In a study of 24 patients with heart failure, an ejection fraction less than 45%, and OSA, patients were randomized to a control group for medical treatment or medical treatment and nasal CPAP for 1 month.⁸ In the CPAP group, mean systolic blood pressure and heart rate were reduced, resulting in an improved ejection fraction compared with baseline, as well as compared with patients in the control group.

In patients with heart failure (N = 66) with and without Cheyne-Stokes respirations in central sleep apnea, patients treated with CPAP were found to have a 60% relative risk reduction in mortality-cardiac transplant rate compared with the control group not using CPAP.⁹ Further stratification in this study showed that patients with significant Cheyne-Stokes respirations and central sleep apnea had an improved ejection fraction at 3 months and an 81% reduced mortality-cardiac transplant rate.⁹

Adherence to PAP therapy is a problem in terms of both frequency of use and duration of use per night. A review of randomized control trials of CPAP compliance between 2011 and 2015 found adherence varied widely from 35% to 87%.¹⁰ The average hours of PAP use per night was found to be 5 hours in APPLES.⁴ Patients adherent to PAP therapy at 1 month remained adherent at 1 year, suggesting patients using CPAP for 1 month were more likely to continue use at 1 year.¹⁰ Impediments to PAP use typically involve the facial interface discomfort, lack of humidity, and pressure intolerance.

FEATURES OF PAP DEVICES

Today’s PAP devices have features designed to make them easier to use and more comfortable to improve adherence to therapy. Facial interface options, heated humidifiers, tubing accessories, cleaning devices, reporting of compliance data via telecommunication, and pressure adjustment features of PAP devices may improve patient adherence and comfort, as highlighted in the case scenarios presented below.

Interfaces

Case scenario #1

A 32-year-old woman with moderate sleep apnea complains that her PAP nasal mask is making very loud noises and is disturbing her bed partner. She is a side sleeper and also reports that she wakes with an extremely dry mouth.

Management of the leak could include which of the following?

1. Chin strap
2. Avoidance of facial creams before bedtime
3. CPAP pillow
4. Clean the mask daily
5. All of the above

Answer: All of the above.

There are many types of PAP interfaces such as nasal masks, nasal pillows, nasal cushions, full-face masks, and less frequently used oral and total face masks. The mask interface is a common impediment to use of PAP therapy often due to poor mask fit or leakage.

Nasal masks cover only the nose and require that the mouth remains closed, which can be achieved with the addition of a chin strap. Nasal masks are available in a variety of materials including cloth. Nasal pillows actually go into the nostrils whereas the nasal mask is positioned under the nose. A nasal cushion mask sits under the nose but does not go into the nostrils.

A study by Lanza and colleagues¹¹ evaluated patient comfort with PAP therapy based on the type of nasal interface mask. Patients using nasal pillows had improvement with respect to swollen eyes, discomfort, skin breakdown, and marks on the face compared with patients using nasal masks; however, nasal pillows can cause nostril pain.

Several types of full-face masks are available, some that fit over the bridge of the nose and some that fit just under the nose. A variety of head straps are available to secure full-face masks. One benefit of full-face masks is that air pressure is delivered to both the nose and the mouth, so the mouth can be open or closed. However, the larger surface area of the full-face mask increases the potential for leaks. A study of adherence in 20 patients using CPAP with nasal masks or full-face masks evaluated hours per use, adherence at 12 months, and comfort.¹² Patients using full-face masks had more hours per use, better adherence at 12 months, and more comfort than patients using nasal masks.

Interface skin irritation and leak management. To help combat skin irritation, particularly for patients with rosacea, cloth products are available for use beneath the mask and headgear. Silicone pads for masks that cause pressure on the bridge of the nose can help protect against skin breakdown. Sleeping positions other than the supine position can contribute to mask leak. CPAP pillows are designed to allow patients to sleep in their desired position while maintaining an adequate mask seal. The pillows are shaped or have cutouts that prevent the mask from pushing on the pillow and creating a leak.

Humidification

Case scenario #2

A 54-year-old man with severe sleep apnea recently initiated CPAP therapy. He quickly discontinued use due to nasal congestion.

Which of the following is NOT recommended?

1. Assure adequate heated humidification
2. Assure that the apnea is adequately treated
3. Use of a full-face mask
4. Use of short-acting nasal decongestants
5. Use of a topical nasal steroid

Answer: Use of short-acting nasal decongestants.

Nasal congestion is a common reason for nonadherence to CPAP therapy.¹³ Pressurized air is very drying and can be very uncomfortable. Residual apneic events can even precipitate further congestion. The use of humidification with CPAP can improve patient comfort and compliance. The vast majority of patients use CPAP devices with heated humidifiers. Heated humidification has been found to increase CPAP use and improve daytime sleepiness and feelings of satisfaction and being refreshed compared with cold humidity or no humidity.¹⁴ Cold humidification improved daytime sleepiness and satisfaction, but not to the degree found with heated humidification.

Heated humidifiers are incorporated in the CPAP machine or attach to it. Heated in-line tubing helps with “rain out,” which refers to water condensation inside the tubing and mask associated with CPAP humidification.

Topical decongestants can actually worsen congestion and cause a reflex vasodilation. Topical nasal steroids can be used for nasal congestion and may be beneficial.

The tubing from the PAP device to the facial interface can be a source of irritation to patients due to rubbing against the skin or entanglement. Products to cover the tubing to reduce irritation and avoid entanglement are available. Extra-long tubing is also available.

Cleaning

Some people find cleaning CPAP equipment daunting. Cleaning devices are available and recommended to patients looking for reassurance about how to keep their CPAP equipment clean. There are also CPAP wipes to clean the mask of oils and creams from the skin to improve the mask seal and reduce leaks.

Pressure control

Advanced modalities are available to adjust how pressure is delivered by PAP devices, including ramp, APAP, pressure relief, and BiPAP. Ramp is a feature that delivers a lower pressure at the beginning of the sleep cycle and slowly increases pressure to therapeutic levels. The lower pressure makes it easier for the user to fall asleep and builds to therapeutic pressure once asleep. APAP adjusts the pressure automatically when needed and reduces the pressure when not needed. Pressure relief is a feature that allows the PAP pressure to decrease at the point of expiration. BiPAP gives a distinct pressure on inspiration and a distinctively different and lower pressure at the point of expiration.

Auto-PAP

Case scenario #3

A 52-year-old woman with hypertension and mild sleep apnea has a polysomnogram with an apnea–hypopnea index of 7 events per hour that increase to 32 events per hour in rapid eye movement (REM) sleep. She is on CPAP at 5 cm of water, but complains of waking every 2 hours with a sense of panic and hot flashes.

Which of the following is the most likely cause of her symptoms?

1. An underlying anxiety disorder
2. An underlying heart condition
3. Perimenopausal symptoms
4. Undertreated REM-related apnea
5. None of the above

Answer: While all of these choices can occur, the most likely cause is undertreated REM-related apnea.

What would be the best next step in treatment for this patient?

1. Hormonal replacement therapy
2. Positional therapy in addition to CPAP
3. APAP
4. Anxiolytic medication
5. All of the above

Answer: APAP.

APAP incorporates an algorithm that detects and adjusts to airflow, pressure fluctuations, and airway resistance. The consensus from the American Academy of Sleep Medicine is that APAP is useful in the case of:

• Pressure intolerance
• REM apnea or positional apnea
• Inadequate in lab PAP titration
• Planned weight loss (bariatric surgery)
• Recurrent symptoms after long-term CPAP use.¹⁵

Pressure relief

Case scenario #4

A 45-year-old man with severe sleep apnea uses CPAP at 10 cm of water. He complains of the inability to exhale against the pressure from the device.

What would be the best next step?

1. Set the pressure relief to a maximum of 3
2. Lower the pressure of CPAP and check a download use at a lower pressure
3. BiPAP titration study in the laboratory
4. Switch to BiPAP if insurance allows
5. Change to a different mask

Answer: Set the pressure relief to a maximum of 3.

The CPAP device delivers pressure in conjunction with the patient’s inspiration and expiration. At the point of expiration, there is a decrease in the pressure delivered by the device to make it easier for the user to exhale. Three selectable settings provide flow-based pressure relief with a setting of 1 for the least degree of pressure reduction and a setting of 3 for the greatest degree of pressure reduction.¹⁶

In a study of the effect of PAP with pressure relief, 93 patients were assigned to use APAP without pressure relief, CPAP with pressure relief (C-Flex), or APAP with pressure relief (A-Flex).¹⁶ At 3 and 6 months, patients using A-Flex had the best adherence to therapy.

Quality of life was also examined in this same study.¹⁶ For patients using APAP alone, there was no statistically significant difference in the Epworth Sleepiness Scale measuring daytime sleepiness or the Pittsburgh Sleep Quality Index. However, in patients using A-Flex, daytime sleepiness improved, as did sleep quality, with statistically significant improvement at 3 months.

Bilevel PAP

Case scenario #5

A 62-year-old man with severe sleep apnea uses CPAP set at 17 cm of water and pressure relief set at 3. He stopped using CPAP due to abdominal pain, extreme belching, and pressure intolerance.

What would be the appropriate next step?

1. Use of simethicone
2. Elevate the head while using PAP therapy
3. BiPAP titration study in the laboratory
4. Switching directly to BiPAP if insurance allows
5. All of the above

Answer: All of the above.

BiPAP devices provide 2 distinct pressures, one for inhalation and one for exhalation. BiPAP also has the ability to deliver a higher overall pressure. A CPAP device typically has a maximum pressure of 20 cm of water, but BiPAP has a maximum pressure of 25 cm of water on inspiration. BiPAP may be helpful in patients with air aphasia and extreme belching. If a patient cannot tolerate CPAP because of the pressure, and if C-Flex has not alleviated the problem, BiPAP would be the next step.

The effectiveness and level of comfort of BiPAP compared with CPAP for the treatment of OSA was evaluated by the American Academy of Sleep Medicine.² The analysis of 7 randomized control trials reporting level I and II evidence found that BiPAP was as effective as CPAP in the treatment of OSA in patients with no comorbidities. For patients with OSA and comorbidities, a level III evidence study reported an increased level of comfort in patients using BiPAP.

Innovative strategies and approaches focusing on patient factors affecting PAP adherence include motivational interviewing, motivational enhancement, telemedicine, and desensitization techniques.

Motivational interviews and enhancement

Motivational interviewing and motivational enhancement were first used to help with alcohol abuse.¹⁷ Motivational interviewing is goal-oriented, patient-centered counseling to elicit a particular behavioral change. The goal is to explore and resolve ambivalence, increase engagement, and evoke a positive response and perspective that builds momentum and results in action.

Motivational enhancement and motivational engagement in the use of PAP therapy were evaluated in the Patient Engagement Study.¹⁸ Patients were assigned to usual care (n = 85,358) or active patient engagement (APE) (n = 42,679). Usual care involved diagnosis of apnea, initiation of CPAP, and follow-up, whereas APE included daily feedback (ie, daily scores of apnea–hypopnea index, mask leaks, hours used), positive praise messages, and personal coaching assistance. Overall adherence for patients assigned to APE was 87% compared with 70% in the usual-care group. The hours of use per night also increased for patients in the APE group.

The Best Apnea Interventions for Research trial randomized patients with or at risk of cardiovascular disease (N = 169) to CPAP alone or CPAP with motivational enhancements for 6 months.¹⁹ Motivational enhancements and interventions included brief in-person and phone interventions. An overall average difference of 99 minutes per night improvement in CPAP use was reported in the motivational enhancement group compared with CPAP alone.

The Motivational Interviewing Nurse Therapy study trained nurses in motivational interviewing and randomized 106 patients with newly diagnosed OSA to CPAP alone or CPAP plus motivational interviews.²⁰ Motivational interviews involved 3 sessions: 1 to build motivation prior to the CPAP titration, 1 to strengthen the commitment to achieve the prescribed time, and a booster session 1 month after CPAP setup. Adherence was found to improve at 1, 2, and 3 months in the motivational interview group; however, no difference between the 2 groups in adherence was noted at 12 months.

Telemedicine

The role of telemedicine in improving adherence with CPAP therapy was evaluated in 75 patients with moderate to severe apnea randomized to APAP alone or with phone call support from a research coordinator.²¹ Phone calls occurred 2 days after device setup, and daily monitoring of several factors was done via modem. Patients were contacted if the mask was leaking more than 30% of the night, use was less than 4 hours per night on 2 consecutive nights, the apnea–hypopnea index was greater than 10, or the average pressure needed was higher than 16 cm of water. Statistically significant improvement was found in the telemedicine group in mean adherence, minutes used per day, and mean amount of time spent with the patients.

Desensitization to PAP therapy

Case scenario #6

A 33-year-old woman with a history of anxiety and depression and a remote history of abuse as a child was diagnosed with severe apnea. When she tries to use her CPAP, she has a sense of panic and cannot proceed.

Which of the following has NOT been shown to be beneficial in this situation?

1. Psychologist for behavioral therapy
2. Desensitization protocol
3. PAP “NAP”
4. Short-acting hypnotics
5. None of the above

Answer: Short-acting hypnotics.

The short-acting hypnotic zaleplon (Sonata) was evaluated in a 1-month study of 88 patients compared with placebo control, and no difference was found between the 2 groups in measures of adherence to therapy or symptoms.²²

PAP NAP. For some people, at-home desensitization is not enough, and a sleep lab session may be needed. A PAP NAP is a daytime study conducted in the sleep lab. Patients do not necessarily sleep, but work with a technologist with a minimal hookup to polysomnography equipment on mask desensitization, as well as biofeedback techniques. PAP NAPs are indicated for patients with claustrophobia, anxiety surrounding PAP therapy, or pressure intolerance.

A study of 99 patients with moderate to severe apnea and insomnia and concomitant psychiatric disorders resistant to CPAP evaluated adherence in a group receiving a PAP NAP (n = 39) compared with a control group (n = 60).²³ The PAP NAP group had marked improvement in completion of CPAP titration in the lab, filling the CPAP prescription, and using CPAP more than 5 days a week and more than 4 hours a night.

A new innovative concept called the Sleep Apnea Patient-Centered Outcomes Network is a collaborative group that includes patients, researchers, and clinicians.²⁴ The group addresses issues such as cost, outcomes, and value in the diagnosis and treatment of sleep apnea. A patient-centered website provides forums, education, and data collection capability for researchers (myapnea.org).

SUMMARY

PAP therapy is the gold standard for treatment of patients with moderate to severe OSA, though poor adherence to PAP therapy is a persistent problem. Advanced features in PAP devices such as APAP and other innovative strategies like motivational enhancement and desensitization protocols and PAP NAP are being used to address poor adherence. More randomized controlled trials are needed to evaluate PAP for sleep apnea.

EFFICACY OF PAP THERAPY

The American Academy of Sleep Medicine practice guidelines for PAP are based on 342 articles, most rated as evidence levels I and II, concluding that CPAP is superior to conservative treatment to:

• Eliminate respiratory disturbances
• Reduce the apnea–hypopnea index
• Decrease the arousal index on electroencephalogram
• Increase in the total amount of slow-wave or N3 sleep
• Reduce daytime sleepiness.²

These practice parameters are based on evidence of improved daytime sleepiness and reduced incidence of cardiovascular events in patients with moderate to severe obstructive sleep apnea (OSA) treated with PAP. The evidence is less clear for neurocognitive markers and cardiovascular events in the treatment of patients with mild sleep apnea.

Sleepiness

A study evaluated sleepiness outcomes in 149 patients with severe sleep apnea with an average apnea–hypopnea index of 69 relative to the duration of nightly CPAP use. Sleepiness was measured using the Functional Outcomes of Sleep Questionnaire, Epworth Sleepiness Scale, and Multiple Sleep Latency Test. Results suggest that a greater percentage of patients had improved daytime sleepiness as the total hours of sleep using CPAP increased.³

The Apnea Positive Pressure Long-term Efficacy Study (APPLES) was a 6-month, multicenter, randomized study of neurocognitive function in patients with OSA (N = 1,098).⁴ Subjective sleepiness as measured by the Epworth Sleepiness Scale showed statistically significant improvement at 2 and 6 months for patients with moderate to severe OSA using CPAP. Objective sleepiness as measured by the Maintenance of Wakefulness Test showed statistically significant improvement (ie, improved daytime alertness) at 2 and 6 months for patients with severe OSA using CPAP.

Neurocognitive function

APPLES also tested for attention and psycho­motor function as well as verbal learning and memory, though no statistically significant improvements were found in these parameters.⁴ Executive function and frontal lobe function showed transient improvement at 2 months in patients with severe sleep apnea using CPAP, but the improvement was not statistically significant at 6 months.

Cardiovascular outcomes

Hypertension and cardiovascular disease. Use of CPAP therapy reduces blood pressure in individuals with hypertension. A study of 32 patients who had a baseline polysomnography with 19 hours of continuous mean arterial blood pressure monitoring were treated with therapeutic CPAP (n = 16) or subtherapeutic CPAP (n = 16).⁵ Therapeutic treatment with CPAP for patients with moderate to severe OSA resulted in statistically significant reductions in mean arterial pressure for both systolic and diastolic pressures. The blood pressure reductions achieved are estimated to reduce coronary artery diseases by 37% and stroke by 56%.⁵

The risk of cardiovascular events in men with severe sleep apnea is high but mitigated by the use of CPAP. In a cohort of 1,651 men, untreated severe sleep apnea resulted in a threefold increase in the rate of cardiovascular events per 1,000 patient-years compared with 4 other groups: a control group, men who snore, men with untreated mild to moderate sleep apnea, and men with OSA using CPAP.⁶ However, when men with severe sleep apnea use CPAP, the risk of cardiovascular events is reduced to the rate in men who snore.

Atrial fibrillation. In patients with atrial fibrillation treated with direct-current cardioversion-
defibrillation, the recurrence of atrial fibrillation at 12 months was greater in patients with untreated OSA (82%) compared with a control group (53%) and patients treated for OSA (42%).⁷

Heart failure. In a study of 24 patients with heart failure, an ejection fraction less than 45%, and OSA, patients were randomized to a control group for medical treatment or medical treatment and nasal CPAP for 1 month.⁸ In the CPAP group, mean systolic blood pressure and heart rate were reduced, resulting in an improved ejection fraction compared with baseline, as well as compared with patients in the control group.

In patients with heart failure (N = 66) with and without Cheyne-Stokes respirations in central sleep apnea, patients treated with CPAP were found to have a 60% relative risk reduction in mortality-cardiac transplant rate compared with the control group not using CPAP.⁹ Further stratification in this study showed that patients with significant Cheyne-Stokes respirations and central sleep apnea had an improved ejection fraction at 3 months and an 81% reduced mortality-cardiac transplant rate.⁹

Adherence to PAP therapy is a problem in terms of both frequency of use and duration of use per night. A review of randomized control trials of CPAP compliance between 2011 and 2015 found adherence varied widely from 35% to 87%.¹⁰ The average hours of PAP use per night was found to be 5 hours in APPLES.⁴ Patients adherent to PAP therapy at 1 month remained adherent at 1 year, suggesting patients using CPAP for 1 month were more likely to continue use at 1 year.¹⁰ Impediments to PAP use typically involve the facial interface discomfort, lack of humidity, and pressure intolerance.

FEATURES OF PAP DEVICES

Today’s PAP devices have features designed to make them easier to use and more comfortable to improve adherence to therapy. Facial interface options, heated humidifiers, tubing accessories, cleaning devices, reporting of compliance data via telecommunication, and pressure adjustment features of PAP devices may improve patient adherence and comfort, as highlighted in the case scenarios presented below.

Interfaces

Case scenario #1

A 32-year-old woman with moderate sleep apnea complains that her PAP nasal mask is making very loud noises and is disturbing her bed partner. She is a side sleeper and also reports that she wakes with an extremely dry mouth.

Management of the leak could include which of the following?

1. Chin strap
2. Avoidance of facial creams before bedtime
3. CPAP pillow
4. Clean the mask daily
5. All of the above

Answer: All of the above.

There are many types of PAP interfaces such as nasal masks, nasal pillows, nasal cushions, full-face masks, and less frequently used oral and total face masks. The mask interface is a common impediment to use of PAP therapy often due to poor mask fit or leakage.

Nasal masks cover only the nose and require that the mouth remains closed, which can be achieved with the addition of a chin strap. Nasal masks are available in a variety of materials including cloth. Nasal pillows actually go into the nostrils whereas the nasal mask is positioned under the nose. A nasal cushion mask sits under the nose but does not go into the nostrils.

A study by Lanza and colleagues¹¹ evaluated patient comfort with PAP therapy based on the type of nasal interface mask. Patients using nasal pillows had improvement with respect to swollen eyes, discomfort, skin breakdown, and marks on the face compared with patients using nasal masks; however, nasal pillows can cause nostril pain.

Several types of full-face masks are available, some that fit over the bridge of the nose and some that fit just under the nose. A variety of head straps are available to secure full-face masks. One benefit of full-face masks is that air pressure is delivered to both the nose and the mouth, so the mouth can be open or closed. However, the larger surface area of the full-face mask increases the potential for leaks. A study of adherence in 20 patients using CPAP with nasal masks or full-face masks evaluated hours per use, adherence at 12 months, and comfort.¹² Patients using full-face masks had more hours per use, better adherence at 12 months, and more comfort than patients using nasal masks.

Interface skin irritation and leak management. To help combat skin irritation, particularly for patients with rosacea, cloth products are available for use beneath the mask and headgear. Silicone pads for masks that cause pressure on the bridge of the nose can help protect against skin breakdown. Sleeping positions other than the supine position can contribute to mask leak. CPAP pillows are designed to allow patients to sleep in their desired position while maintaining an adequate mask seal. The pillows are shaped or have cutouts that prevent the mask from pushing on the pillow and creating a leak.

Humidification

Case scenario #2

A 54-year-old man with severe sleep apnea recently initiated CPAP therapy. He quickly discontinued use due to nasal congestion.

Which of the following is NOT recommended?

1. Assure adequate heated humidification
2. Assure that the apnea is adequately treated
3. Use of a full-face mask
4. Use of short-acting nasal decongestants
5. Use of a topical nasal steroid

Answer: Use of short-acting nasal decongestants.

Nasal congestion is a common reason for nonadherence to CPAP therapy.¹³ Pressurized air is very drying and can be very uncomfortable. Residual apneic events can even precipitate further congestion. The use of humidification with CPAP can improve patient comfort and compliance. The vast majority of patients use CPAP devices with heated humidifiers. Heated humidification has been found to increase CPAP use and improve daytime sleepiness and feelings of satisfaction and being refreshed compared with cold humidity or no humidity.¹⁴ Cold humidification improved daytime sleepiness and satisfaction, but not to the degree found with heated humidification.

Heated humidifiers are incorporated in the CPAP machine or attach to it. Heated in-line tubing helps with “rain out,” which refers to water condensation inside the tubing and mask associated with CPAP humidification.

Topical decongestants can actually worsen congestion and cause a reflex vasodilation. Topical nasal steroids can be used for nasal congestion and may be beneficial.

The tubing from the PAP device to the facial interface can be a source of irritation to patients due to rubbing against the skin or entanglement. Products to cover the tubing to reduce irritation and avoid entanglement are available. Extra-long tubing is also available.

Cleaning

Some people find cleaning CPAP equipment daunting. Cleaning devices are available and recommended to patients looking for reassurance about how to keep their CPAP equipment clean. There are also CPAP wipes to clean the mask of oils and creams from the skin to improve the mask seal and reduce leaks.

Pressure control

Advanced modalities are available to adjust how pressure is delivered by PAP devices, including ramp, APAP, pressure relief, and BiPAP. Ramp is a feature that delivers a lower pressure at the beginning of the sleep cycle and slowly increases pressure to therapeutic levels. The lower pressure makes it easier for the user to fall asleep and builds to therapeutic pressure once asleep. APAP adjusts the pressure automatically when needed and reduces the pressure when not needed. Pressure relief is a feature that allows the PAP pressure to decrease at the point of expiration. BiPAP gives a distinct pressure on inspiration and a distinctively different and lower pressure at the point of expiration.

Auto-PAP

Case scenario #3

A 52-year-old woman with hypertension and mild sleep apnea has a polysomnogram with an apnea–hypopnea index of 7 events per hour that increase to 32 events per hour in rapid eye movement (REM) sleep. She is on CPAP at 5 cm of water, but complains of waking every 2 hours with a sense of panic and hot flashes.

Which of the following is the most likely cause of her symptoms?

1. An underlying anxiety disorder
2. An underlying heart condition
3. Perimenopausal symptoms
4. Undertreated REM-related apnea
5. None of the above

Answer: While all of these choices can occur, the most likely cause is undertreated REM-related apnea.

What would be the best next step in treatment for this patient?

1. Hormonal replacement therapy
2. Positional therapy in addition to CPAP
3. APAP
4. Anxiolytic medication
5. All of the above

Answer: APAP.

APAP incorporates an algorithm that detects and adjusts to airflow, pressure fluctuations, and airway resistance. The consensus from the American Academy of Sleep Medicine is that APAP is useful in the case of:

• Pressure intolerance
• REM apnea or positional apnea
• Inadequate in lab PAP titration
• Planned weight loss (bariatric surgery)
• Recurrent symptoms after long-term CPAP use.¹⁵

Pressure relief

Case scenario #4

A 45-year-old man with severe sleep apnea uses CPAP at 10 cm of water. He complains of the inability to exhale against the pressure from the device.

What would be the best next step?

1. Set the pressure relief to a maximum of 3
2. Lower the pressure of CPAP and check a download use at a lower pressure
3. BiPAP titration study in the laboratory
4. Switch to BiPAP if insurance allows
5. Change to a different mask

Answer: Set the pressure relief to a maximum of 3.

The CPAP device delivers pressure in conjunction with the patient’s inspiration and expiration. At the point of expiration, there is a decrease in the pressure delivered by the device to make it easier for the user to exhale. Three selectable settings provide flow-based pressure relief with a setting of 1 for the least degree of pressure reduction and a setting of 3 for the greatest degree of pressure reduction.¹⁶

In a study of the effect of PAP with pressure relief, 93 patients were assigned to use APAP without pressure relief, CPAP with pressure relief (C-Flex), or APAP with pressure relief (A-Flex).¹⁶ At 3 and 6 months, patients using A-Flex had the best adherence to therapy.

Quality of life was also examined in this same study.¹⁶ For patients using APAP alone, there was no statistically significant difference in the Epworth Sleepiness Scale measuring daytime sleepiness or the Pittsburgh Sleep Quality Index. However, in patients using A-Flex, daytime sleepiness improved, as did sleep quality, with statistically significant improvement at 3 months.

Bilevel PAP

Case scenario #5

A 62-year-old man with severe sleep apnea uses CPAP set at 17 cm of water and pressure relief set at 3. He stopped using CPAP due to abdominal pain, extreme belching, and pressure intolerance.

What would be the appropriate next step?

1. Use of simethicone
2. Elevate the head while using PAP therapy
3. BiPAP titration study in the laboratory
4. Switching directly to BiPAP if insurance allows
5. All of the above

Answer: All of the above.

BiPAP devices provide 2 distinct pressures, one for inhalation and one for exhalation. BiPAP also has the ability to deliver a higher overall pressure. A CPAP device typically has a maximum pressure of 20 cm of water, but BiPAP has a maximum pressure of 25 cm of water on inspiration. BiPAP may be helpful in patients with air aphasia and extreme belching. If a patient cannot tolerate CPAP because of the pressure, and if C-Flex has not alleviated the problem, BiPAP would be the next step.

The effectiveness and level of comfort of BiPAP compared with CPAP for the treatment of OSA was evaluated by the American Academy of Sleep Medicine.² The analysis of 7 randomized control trials reporting level I and II evidence found that BiPAP was as effective as CPAP in the treatment of OSA in patients with no comorbidities. For patients with OSA and comorbidities, a level III evidence study reported an increased level of comfort in patients using BiPAP.

Innovative strategies and approaches focusing on patient factors affecting PAP adherence include motivational interviewing, motivational enhancement, telemedicine, and desensitization techniques.

Motivational interviews and enhancement

Motivational interviewing and motivational enhancement were first used to help with alcohol abuse.¹⁷ Motivational interviewing is goal-oriented, patient-centered counseling to elicit a particular behavioral change. The goal is to explore and resolve ambivalence, increase engagement, and evoke a positive response and perspective that builds momentum and results in action.

Motivational enhancement and motivational engagement in the use of PAP therapy were evaluated in the Patient Engagement Study.¹⁸ Patients were assigned to usual care (n = 85,358) or active patient engagement (APE) (n = 42,679). Usual care involved diagnosis of apnea, initiation of CPAP, and follow-up, whereas APE included daily feedback (ie, daily scores of apnea–hypopnea index, mask leaks, hours used), positive praise messages, and personal coaching assistance. Overall adherence for patients assigned to APE was 87% compared with 70% in the usual-care group. The hours of use per night also increased for patients in the APE group.

The Best Apnea Interventions for Research trial randomized patients with or at risk of cardiovascular disease (N = 169) to CPAP alone or CPAP with motivational enhancements for 6 months.¹⁹ Motivational enhancements and interventions included brief in-person and phone interventions. An overall average difference of 99 minutes per night improvement in CPAP use was reported in the motivational enhancement group compared with CPAP alone.

The Motivational Interviewing Nurse Therapy study trained nurses in motivational interviewing and randomized 106 patients with newly diagnosed OSA to CPAP alone or CPAP plus motivational interviews.²⁰ Motivational interviews involved 3 sessions: 1 to build motivation prior to the CPAP titration, 1 to strengthen the commitment to achieve the prescribed time, and a booster session 1 month after CPAP setup. Adherence was found to improve at 1, 2, and 3 months in the motivational interview group; however, no difference between the 2 groups in adherence was noted at 12 months.

Telemedicine

The role of telemedicine in improving adherence with CPAP therapy was evaluated in 75 patients with moderate to severe apnea randomized to APAP alone or with phone call support from a research coordinator.²¹ Phone calls occurred 2 days after device setup, and daily monitoring of several factors was done via modem. Patients were contacted if the mask was leaking more than 30% of the night, use was less than 4 hours per night on 2 consecutive nights, the apnea–hypopnea index was greater than 10, or the average pressure needed was higher than 16 cm of water. Statistically significant improvement was found in the telemedicine group in mean adherence, minutes used per day, and mean amount of time spent with the patients.

Desensitization to PAP therapy

Case scenario #6

A 33-year-old woman with a history of anxiety and depression and a remote history of abuse as a child was diagnosed with severe apnea. When she tries to use her CPAP, she has a sense of panic and cannot proceed.

Which of the following has NOT been shown to be beneficial in this situation?

1. Psychologist for behavioral therapy
2. Desensitization protocol
3. PAP “NAP”
4. Short-acting hypnotics
5. None of the above

Answer: Short-acting hypnotics.

The short-acting hypnotic zaleplon (Sonata) was evaluated in a 1-month study of 88 patients compared with placebo control, and no difference was found between the 2 groups in measures of adherence to therapy or symptoms.²²

PAP NAP. For some people, at-home desensitization is not enough, and a sleep lab session may be needed. A PAP NAP is a daytime study conducted in the sleep lab. Patients do not necessarily sleep, but work with a technologist with a minimal hookup to polysomnography equipment on mask desensitization, as well as biofeedback techniques. PAP NAPs are indicated for patients with claustrophobia, anxiety surrounding PAP therapy, or pressure intolerance.

A study of 99 patients with moderate to severe apnea and insomnia and concomitant psychiatric disorders resistant to CPAP evaluated adherence in a group receiving a PAP NAP (n = 39) compared with a control group (n = 60).²³ The PAP NAP group had marked improvement in completion of CPAP titration in the lab, filling the CPAP prescription, and using CPAP more than 5 days a week and more than 4 hours a night.

A new innovative concept called the Sleep Apnea Patient-Centered Outcomes Network is a collaborative group that includes patients, researchers, and clinicians.²⁴ The group addresses issues such as cost, outcomes, and value in the diagnosis and treatment of sleep apnea. A patient-centered website provides forums, education, and data collection capability for researchers (myapnea.org).

SUMMARY

PAP therapy is the gold standard for treatment of patients with moderate to severe OSA, though poor adherence to PAP therapy is a persistent problem. Advanced features in PAP devices such as APAP and other innovative strategies like motivational enhancement and desensitization protocols and PAP NAP are being used to address poor adherence. More randomized controlled trials are needed to evaluate PAP for sleep apnea.

EFFICACY OF PAP THERAPY

The American Academy of Sleep Medicine practice guidelines for PAP are based on 342 articles, most rated as evidence levels I and II, concluding that CPAP is superior to conservative treatment to:

• Eliminate respiratory disturbances
• Reduce the apnea–hypopnea index
• Decrease the arousal index on electroencephalogram
• Increase in the total amount of slow-wave or N3 sleep
• Reduce daytime sleepiness.²

These practice parameters are based on evidence of improved daytime sleepiness and reduced incidence of cardiovascular events in patients with moderate to severe obstructive sleep apnea (OSA) treated with PAP. The evidence is less clear for neurocognitive markers and cardiovascular events in the treatment of patients with mild sleep apnea.

Sleepiness

A study evaluated sleepiness outcomes in 149 patients with severe sleep apnea with an average apnea–hypopnea index of 69 relative to the duration of nightly CPAP use. Sleepiness was measured using the Functional Outcomes of Sleep Questionnaire, Epworth Sleepiness Scale, and Multiple Sleep Latency Test. Results suggest that a greater percentage of patients had improved daytime sleepiness as the total hours of sleep using CPAP increased.³

The Apnea Positive Pressure Long-term Efficacy Study (APPLES) was a 6-month, multicenter, randomized study of neurocognitive function in patients with OSA (N = 1,098).⁴ Subjective sleepiness as measured by the Epworth Sleepiness Scale showed statistically significant improvement at 2 and 6 months for patients with moderate to severe OSA using CPAP. Objective sleepiness as measured by the Maintenance of Wakefulness Test showed statistically significant improvement (ie, improved daytime alertness) at 2 and 6 months for patients with severe OSA using CPAP.

Neurocognitive function

APPLES also tested for attention and psycho­motor function as well as verbal learning and memory, though no statistically significant improvements were found in these parameters.⁴ Executive function and frontal lobe function showed transient improvement at 2 months in patients with severe sleep apnea using CPAP, but the improvement was not statistically significant at 6 months.

Cardiovascular outcomes

Hypertension and cardiovascular disease. Use of CPAP therapy reduces blood pressure in individuals with hypertension. A study of 32 patients who had a baseline polysomnography with 19 hours of continuous mean arterial blood pressure monitoring were treated with therapeutic CPAP (n = 16) or subtherapeutic CPAP (n = 16).⁵ Therapeutic treatment with CPAP for patients with moderate to severe OSA resulted in statistically significant reductions in mean arterial pressure for both systolic and diastolic pressures. The blood pressure reductions achieved are estimated to reduce coronary artery diseases by 37% and stroke by 56%.⁵

The risk of cardiovascular events in men with severe sleep apnea is high but mitigated by the use of CPAP. In a cohort of 1,651 men, untreated severe sleep apnea resulted in a threefold increase in the rate of cardiovascular events per 1,000 patient-years compared with 4 other groups: a control group, men who snore, men with untreated mild to moderate sleep apnea, and men with OSA using CPAP.⁶ However, when men with severe sleep apnea use CPAP, the risk of cardiovascular events is reduced to the rate in men who snore.

Atrial fibrillation. In patients with atrial fibrillation treated with direct-current cardioversion-
defibrillation, the recurrence of atrial fibrillation at 12 months was greater in patients with untreated OSA (82%) compared with a control group (53%) and patients treated for OSA (42%).⁷

Heart failure. In a study of 24 patients with heart failure, an ejection fraction less than 45%, and OSA, patients were randomized to a control group for medical treatment or medical treatment and nasal CPAP for 1 month.⁸ In the CPAP group, mean systolic blood pressure and heart rate were reduced, resulting in an improved ejection fraction compared with baseline, as well as compared with patients in the control group.

In patients with heart failure (N = 66) with and without Cheyne-Stokes respirations in central sleep apnea, patients treated with CPAP were found to have a 60% relative risk reduction in mortality-cardiac transplant rate compared with the control group not using CPAP.⁹ Further stratification in this study showed that patients with significant Cheyne-Stokes respirations and central sleep apnea had an improved ejection fraction at 3 months and an 81% reduced mortality-cardiac transplant rate.⁹

Adherence to PAP therapy is a problem in terms of both frequency of use and duration of use per night. A review of randomized control trials of CPAP compliance between 2011 and 2015 found adherence varied widely from 35% to 87%.¹⁰ The average hours of PAP use per night was found to be 5 hours in APPLES.⁴ Patients adherent to PAP therapy at 1 month remained adherent at 1 year, suggesting patients using CPAP for 1 month were more likely to continue use at 1 year.¹⁰ Impediments to PAP use typically involve the facial interface discomfort, lack of humidity, and pressure intolerance.

FEATURES OF PAP DEVICES

Today’s PAP devices have features designed to make them easier to use and more comfortable to improve adherence to therapy. Facial interface options, heated humidifiers, tubing accessories, cleaning devices, reporting of compliance data via telecommunication, and pressure adjustment features of PAP devices may improve patient adherence and comfort, as highlighted in the case scenarios presented below.

Interfaces

Case scenario #1

A 32-year-old woman with moderate sleep apnea complains that her PAP nasal mask is making very loud noises and is disturbing her bed partner. She is a side sleeper and also reports that she wakes with an extremely dry mouth.

Management of the leak could include which of the following?

1. Chin strap
2. Avoidance of facial creams before bedtime
3. CPAP pillow
4. Clean the mask daily
5. All of the above

Answer: All of the above.

There are many types of PAP interfaces such as nasal masks, nasal pillows, nasal cushions, full-face masks, and less frequently used oral and total face masks. The mask interface is a common impediment to use of PAP therapy often due to poor mask fit or leakage.

Nasal masks cover only the nose and require that the mouth remains closed, which can be achieved with the addition of a chin strap. Nasal masks are available in a variety of materials including cloth. Nasal pillows actually go into the nostrils whereas the nasal mask is positioned under the nose. A nasal cushion mask sits under the nose but does not go into the nostrils.

A study by Lanza and colleagues¹¹ evaluated patient comfort with PAP therapy based on the type of nasal interface mask. Patients using nasal pillows had improvement with respect to swollen eyes, discomfort, skin breakdown, and marks on the face compared with patients using nasal masks; however, nasal pillows can cause nostril pain.

Several types of full-face masks are available, some that fit over the bridge of the nose and some that fit just under the nose. A variety of head straps are available to secure full-face masks. One benefit of full-face masks is that air pressure is delivered to both the nose and the mouth, so the mouth can be open or closed. However, the larger surface area of the full-face mask increases the potential for leaks. A study of adherence in 20 patients using CPAP with nasal masks or full-face masks evaluated hours per use, adherence at 12 months, and comfort.¹² Patients using full-face masks had more hours per use, better adherence at 12 months, and more comfort than patients using nasal masks.

Interface skin irritation and leak management. To help combat skin irritation, particularly for patients with rosacea, cloth products are available for use beneath the mask and headgear. Silicone pads for masks that cause pressure on the bridge of the nose can help protect against skin breakdown. Sleeping positions other than the supine position can contribute to mask leak. CPAP pillows are designed to allow patients to sleep in their desired position while maintaining an adequate mask seal. The pillows are shaped or have cutouts that prevent the mask from pushing on the pillow and creating a leak.

Humidification

Case scenario #2

A 54-year-old man with severe sleep apnea recently initiated CPAP therapy. He quickly discontinued use due to nasal congestion.

Which of the following is NOT recommended?

1. Assure adequate heated humidification
2. Assure that the apnea is adequately treated
3. Use of a full-face mask
4. Use of short-acting nasal decongestants
5. Use of a topical nasal steroid

Answer: Use of short-acting nasal decongestants.

Nasal congestion is a common reason for nonadherence to CPAP therapy.¹³ Pressurized air is very drying and can be very uncomfortable. Residual apneic events can even precipitate further congestion. The use of humidification with CPAP can improve patient comfort and compliance. The vast majority of patients use CPAP devices with heated humidifiers. Heated humidification has been found to increase CPAP use and improve daytime sleepiness and feelings of satisfaction and being refreshed compared with cold humidity or no humidity.¹⁴ Cold humidification improved daytime sleepiness and satisfaction, but not to the degree found with heated humidification.

Heated humidifiers are incorporated in the CPAP machine or attach to it. Heated in-line tubing helps with “rain out,” which refers to water condensation inside the tubing and mask associated with CPAP humidification.

Topical decongestants can actually worsen congestion and cause a reflex vasodilation. Topical nasal steroids can be used for nasal congestion and may be beneficial.

The tubing from the PAP device to the facial interface can be a source of irritation to patients due to rubbing against the skin or entanglement. Products to cover the tubing to reduce irritation and avoid entanglement are available. Extra-long tubing is also available.

Cleaning

Some people find cleaning CPAP equipment daunting. Cleaning devices are available and recommended to patients looking for reassurance about how to keep their CPAP equipment clean. There are also CPAP wipes to clean the mask of oils and creams from the skin to improve the mask seal and reduce leaks.

Pressure control

Advanced modalities are available to adjust how pressure is delivered by PAP devices, including ramp, APAP, pressure relief, and BiPAP. Ramp is a feature that delivers a lower pressure at the beginning of the sleep cycle and slowly increases pressure to therapeutic levels. The lower pressure makes it easier for the user to fall asleep and builds to therapeutic pressure once asleep. APAP adjusts the pressure automatically when needed and reduces the pressure when not needed. Pressure relief is a feature that allows the PAP pressure to decrease at the point of expiration. BiPAP gives a distinct pressure on inspiration and a distinctively different and lower pressure at the point of expiration.

Auto-PAP

Case scenario #3

A 52-year-old woman with hypertension and mild sleep apnea has a polysomnogram with an apnea–hypopnea index of 7 events per hour that increase to 32 events per hour in rapid eye movement (REM) sleep. She is on CPAP at 5 cm of water, but complains of waking every 2 hours with a sense of panic and hot flashes.

Which of the following is the most likely cause of her symptoms?

1. An underlying anxiety disorder
2. An underlying heart condition
3. Perimenopausal symptoms
4. Undertreated REM-related apnea
5. None of the above

Answer: While all of these choices can occur, the most likely cause is undertreated REM-related apnea.

What would be the best next step in treatment for this patient?

1. Hormonal replacement therapy
2. Positional therapy in addition to CPAP
3. APAP
4. Anxiolytic medication
5. All of the above

Answer: APAP.

APAP incorporates an algorithm that detects and adjusts to airflow, pressure fluctuations, and airway resistance. The consensus from the American Academy of Sleep Medicine is that APAP is useful in the case of:

• Pressure intolerance
• REM apnea or positional apnea
• Inadequate in lab PAP titration
• Planned weight loss (bariatric surgery)
• Recurrent symptoms after long-term CPAP use.¹⁵

Pressure relief

Case scenario #4

A 45-year-old man with severe sleep apnea uses CPAP at 10 cm of water. He complains of the inability to exhale against the pressure from the device.

What would be the best next step?

1. Set the pressure relief to a maximum of 3
2. Lower the pressure of CPAP and check a download use at a lower pressure
3. BiPAP titration study in the laboratory
4. Switch to BiPAP if insurance allows
5. Change to a different mask

Answer: Set the pressure relief to a maximum of 3.

The CPAP device delivers pressure in conjunction with the patient’s inspiration and expiration. At the point of expiration, there is a decrease in the pressure delivered by the device to make it easier for the user to exhale. Three selectable settings provide flow-based pressure relief with a setting of 1 for the least degree of pressure reduction and a setting of 3 for the greatest degree of pressure reduction.¹⁶

In a study of the effect of PAP with pressure relief, 93 patients were assigned to use APAP without pressure relief, CPAP with pressure relief (C-Flex), or APAP with pressure relief (A-Flex).¹⁶ At 3 and 6 months, patients using A-Flex had the best adherence to therapy.

Quality of life was also examined in this same study.¹⁶ For patients using APAP alone, there was no statistically significant difference in the Epworth Sleepiness Scale measuring daytime sleepiness or the Pittsburgh Sleep Quality Index. However, in patients using A-Flex, daytime sleepiness improved, as did sleep quality, with statistically significant improvement at 3 months.

Bilevel PAP

Case scenario #5

A 62-year-old man with severe sleep apnea uses CPAP set at 17 cm of water and pressure relief set at 3. He stopped using CPAP due to abdominal pain, extreme belching, and pressure intolerance.

What would be the appropriate next step?

1. Use of simethicone
2. Elevate the head while using PAP therapy
3. BiPAP titration study in the laboratory
4. Switching directly to BiPAP if insurance allows
5. All of the above

Answer: All of the above.

BiPAP devices provide 2 distinct pressures, one for inhalation and one for exhalation. BiPAP also has the ability to deliver a higher overall pressure. A CPAP device typically has a maximum pressure of 20 cm of water, but BiPAP has a maximum pressure of 25 cm of water on inspiration. BiPAP may be helpful in patients with air aphasia and extreme belching. If a patient cannot tolerate CPAP because of the pressure, and if C-Flex has not alleviated the problem, BiPAP would be the next step.

The effectiveness and level of comfort of BiPAP compared with CPAP for the treatment of OSA was evaluated by the American Academy of Sleep Medicine.² The analysis of 7 randomized control trials reporting level I and II evidence found that BiPAP was as effective as CPAP in the treatment of OSA in patients with no comorbidities. For patients with OSA and comorbidities, a level III evidence study reported an increased level of comfort in patients using BiPAP.

Innovative strategies and approaches focusing on patient factors affecting PAP adherence include motivational interviewing, motivational enhancement, telemedicine, and desensitization techniques.

Motivational interviews and enhancement

Motivational interviewing and motivational enhancement were first used to help with alcohol abuse.¹⁷ Motivational interviewing is goal-oriented, patient-centered counseling to elicit a particular behavioral change. The goal is to explore and resolve ambivalence, increase engagement, and evoke a positive response and perspective that builds momentum and results in action.

Motivational enhancement and motivational engagement in the use of PAP therapy were evaluated in the Patient Engagement Study.¹⁸ Patients were assigned to usual care (n = 85,358) or active patient engagement (APE) (n = 42,679). Usual care involved diagnosis of apnea, initiation of CPAP, and follow-up, whereas APE included daily feedback (ie, daily scores of apnea–hypopnea index, mask leaks, hours used), positive praise messages, and personal coaching assistance. Overall adherence for patients assigned to APE was 87% compared with 70% in the usual-care group. The hours of use per night also increased for patients in the APE group.

The Best Apnea Interventions for Research trial randomized patients with or at risk of cardiovascular disease (N = 169) to CPAP alone or CPAP with motivational enhancements for 6 months.¹⁹ Motivational enhancements and interventions included brief in-person and phone interventions. An overall average difference of 99 minutes per night improvement in CPAP use was reported in the motivational enhancement group compared with CPAP alone.

The Motivational Interviewing Nurse Therapy study trained nurses in motivational interviewing and randomized 106 patients with newly diagnosed OSA to CPAP alone or CPAP plus motivational interviews.²⁰ Motivational interviews involved 3 sessions: 1 to build motivation prior to the CPAP titration, 1 to strengthen the commitment to achieve the prescribed time, and a booster session 1 month after CPAP setup. Adherence was found to improve at 1, 2, and 3 months in the motivational interview group; however, no difference between the 2 groups in adherence was noted at 12 months.

Telemedicine

The role of telemedicine in improving adherence with CPAP therapy was evaluated in 75 patients with moderate to severe apnea randomized to APAP alone or with phone call support from a research coordinator.²¹ Phone calls occurred 2 days after device setup, and daily monitoring of several factors was done via modem. Patients were contacted if the mask was leaking more than 30% of the night, use was less than 4 hours per night on 2 consecutive nights, the apnea–hypopnea index was greater than 10, or the average pressure needed was higher than 16 cm of water. Statistically significant improvement was found in the telemedicine group in mean adherence, minutes used per day, and mean amount of time spent with the patients.

Desensitization to PAP therapy

Case scenario #6

A 33-year-old woman with a history of anxiety and depression and a remote history of abuse as a child was diagnosed with severe apnea. When she tries to use her CPAP, she has a sense of panic and cannot proceed.

Which of the following has NOT been shown to be beneficial in this situation?

1. Psychologist for behavioral therapy
2. Desensitization protocol
3. PAP “NAP”
4. Short-acting hypnotics
5. None of the above

Answer: Short-acting hypnotics.

The short-acting hypnotic zaleplon (Sonata) was evaluated in a 1-month study of 88 patients compared with placebo control, and no difference was found between the 2 groups in measures of adherence to therapy or symptoms.²²

PAP NAP. For some people, at-home desensitization is not enough, and a sleep lab session may be needed. A PAP NAP is a daytime study conducted in the sleep lab. Patients do not necessarily sleep, but work with a technologist with a minimal hookup to polysomnography equipment on mask desensitization, as well as biofeedback techniques. PAP NAPs are indicated for patients with claustrophobia, anxiety surrounding PAP therapy, or pressure intolerance.

A study of 99 patients with moderate to severe apnea and insomnia and concomitant psychiatric disorders resistant to CPAP evaluated adherence in a group receiving a PAP NAP (n = 39) compared with a control group (n = 60).²³ The PAP NAP group had marked improvement in completion of CPAP titration in the lab, filling the CPAP prescription, and using CPAP more than 5 days a week and more than 4 hours a night.

A new innovative concept called the Sleep Apnea Patient-Centered Outcomes Network is a collaborative group that includes patients, researchers, and clinicians.²⁴ The group addresses issues such as cost, outcomes, and value in the diagnosis and treatment of sleep apnea. A patient-centered website provides forums, education, and data collection capability for researchers (myapnea.org).

SUMMARY

PAP therapy is the gold standard for treatment of patients with moderate to severe OSA, though poor adherence to PAP therapy is a persistent problem. Advanced features in PAP devices such as APAP and other innovative strategies like motivational enhancement and desensitization protocols and PAP NAP are being used to address poor adherence. More randomized controlled trials are needed to evaluate PAP for sleep apnea.