Correct Scoring of Hypopneas in Obstructive Sleep Apnea Reduces Cardiovascular Morbidity

James M. Parish, MD¹

David Baratz, MD²

¹Mayo Clinic Arizona; Phoenix, AZ USA

²Pulmonary Associates, Phoenix, AZ USA

Obstructive Sleep Apnea (OSA) is a life-altering disease with a prevalence of 10% in men and 9% in women (1). In some groups (severe obesity, BMI > 40 kg/m2) the prevalence may be as high as 40% (2). One of the most controversial areas in the field of sleep medicine for many years has been the definition of the syndrome. Investigators who first identified OSA created the apnea index (AI), the number of apnea events per hour. An apnea was defined as a complete cessation of airflow for at least 10 seconds. When continuous positive airway pressure (CPAP) treatment for OSA was first introduced, a definition that third-party payors, such as the Center for Medicare and Medicaid Services (CMS), could use to determine which patients qualified for treatment was needed. The definition at that time was 30 apnea events during a 6-hour recording, which corresponded to an AI of 5 events per hour. As further information developed about the syndrome of OSA, the presence of the hypopnea was recognized. A hypopnea was an event that was not a complete cessation of airflow, but rather was a reduction in airflow associated with either a reduction of oxygen saturation and/or an arousal from sleep. Hypopneas were found to have the same clinical significance as apneas. However, controversy surrounded the exact definition of hypopnea. What percentage reduction in airflow? What degree of desaturation, 3%, 4%, other? (3) And what was the exact definition of arousal? Additionally, at this time, CMS would not recognize the use of hypopneas in the definition of OSA for the purpose of qualifying patients for the use of CPAP and a result, many patients with predominantly hypopneas did not meet the qualifications for CPAP.

Subsequently, an agreement between the sleep community and CMS was reached utilizing the definition of hypopnea of a reduction of airflow to 30% of baseline and a 4% oxygen desaturation (4). This definition was based on findings from the Sleep Heart Health Study demonstrating significant cardiovascular effects in patients with obstructive sleep apnea/hypopnea syndrome utilizing this definition. The association of hypopnea with arousal was left out of this definition at this time because there was poor reproducibility in scoring. While the benefit of this agreement was the inclusion of hypopneas which allowed more patients to qualify for PAP therapy, there was a large group of individuals with hypopneas with 3% desaturation and/or an arousal who did not meet the criteria for therapy.

In 2012 the American Academy of Sleep Medicine (AASM) recommended that the hypopnea definition include any decrease in airflow by at least 30% from the baseline with an oxygen desaturation of at least 3% or an arousal from sleep (5,6). This definition often forced many sleep laboratories to score studies twice, once using the 3% rule and the other using the 4% rule. The 3%-4% controversy has continued for many years.

Since then CMS and other payors has not adopted the recommendation of the AASM primarily because of lack of evidence that a 3% decrease is associated with cardiovascular disease and relied on a more restrictive definition of OSA fewer patients with OSA (as defined by the AASM) have been able to obtain life changing therapy such as CPAP. In the view of many, this has increased the risk of developing cardiovascular disease.

In this issue of SWJPCC an article by Quan et al., “The Association Between Obstructive Sleep Apnea Defined by 3 Percent Oxygen Desaturation or Arousal Definition and Self-Reported Cardiovascular Disease in the Sleep Heart Health Study” demonstrates that employing a definition of hypopnea utilizing a 3% reduction in the oxygen desaturation results in an equivalent incidence of cardiovascular disease (CVD) or coronary heart disease (CHD) as the more restrictive 4% definition (7). The shows that in patients followed in the Sleep Heart Health Study (SHHS) that 6307 participants developed CVD/CHD at equal rates based on odds ratios and 95% confidence intervals.  The SHHS was a prospective multicenter cohort study designed to investigate the relationship between OSA and CVD (8).  6441 subjects 40 years and older were recruited in 1995 to undergo polysomnography, having demographic information taken and then self-report if they were ever told by a doctor that they had angina, heart attack, heart failure, stroke or undergone coronary bypass surgery or coronary angioplasty. CHD or CVD was defined as a positive response to one or more of these conditions or procedures. In addition, the presence of hypertension, diabetes, depression, insomnia and hypersomnia in these subjects was assessed.

In this current analysis of the SHHS 3326 participants were found not to have OSA by the 4% CMS rule. Using the 3% AASM definition of hypopnea, 2247 of the 3326 participants were found to have OSA. Participants that were not diagnosed by the 4% rule had OSA ranging in the mild to severe categories. This study suggests that the regulatory requirement by the CMS of using a 4% decrease in oxygen desaturation denies a substantial number of patients the opportunity for treatment of their OSA and may worsen cardiovascular disease or coronary heart disease.

This paper is the first to assess the association of the 3% criteria in the risk of developing CVD/CHD in patients with OSA. The importance of this paper cannot be underestimated.  There are no other studies that have been done or are being done that investigate the risk between OSA or cardiovascular disease using polysomnographic measurements. By utilizing the 3% rule in clinical practice a much larger number of patients would meet the diagnostic criteria of OSA and be eligible to receive treatment.

Treatment of OSA with CPAP has been shown to reduce the severity of CVD, CHD, diabetes, motor vehicle accidents. It also improves daytime alertness, concentration, emotional stability, reduces snoring, and reduces medical expenses (9-11).

The current study provides the necessary information to help resolve the ongoing controversy. The studies data is very robust, using the well-known Sleep Heart Health study. A limitation of the study is that it relies on self-reported history of cardiovascular disease, which is subject to recall bias, but the data is otherwise very strong and robust. Also, some of the correlations are less statistically significant when adjusted for other co-variates.

This study provides proof that a large number of patients with symptomatic and dangerous OSA have been undertreated. It calls for a change in the policy by the CMS and all other payors to provide therapy for patients with OSA based on the American Academy of Sleep Medicine criteria using a 3% reduction in oxygen saturation to score hypopneas.

References

1. Peppard PE, Young T, Barnet JH, Palta M, Hagen EW, Hla KM. Increased prevalence of sleep-disordered breathing in adults. Am J Epidemiol. 2013 May 1;177(9):1006-14. [CrossRef] [PubMed]
2. Rajala R, Partinen M, Sane T, Pelkonen R, Huikuri K, Seppäläinen AM. Obstructive sleep apnoea syndrome in morbidly obese patients. J Intern Med. 1991 Aug;230(2):125-9. [CrossRef] [PubMed]
3. Redline S, Sanders M. Hypopnea, a floating metric: implications for prevalence, morbidity estimates, and case finding. Sleep. 1997 Dec;20(12):1209-17. [CrossRef] [PubMed]
4. Meoli AL, Casey KR, Clark RW, Coleman JA Jr, Fayle RW, Troell RJ, Iber C; Clinical Practice Review Committee. Hypopnea in sleep-disordered breathing in adults. Sleep. 2001 Jun 15;24(4):469-70. [PubMed]
5. Anonymous. CPAP for Obstructive Sleep Apnea Updated 2020. https://www.cms.gov/Medicare/Coverage/Coverage-with-Evidence-Development/CPAP. 
6. Berry RB, Budhiraja R, Gottlieb DJ, Gozal D, Iber C, Kapur VK, Marcus CL, Mehra R, Parthasarathy S, Quan SF, Redline S, Strohl KP, Davidson Ward SL, Tangredi MM; American Academy of Sleep Medicine. Rules for scoring respiratory events in sleep: update of the 2007 AASM Manual for the Scoring of Sleep and Associated Events. Deliberations of the Sleep Apnea Definitions Task Force of the American Academy of Sleep Medicine. J Clin Sleep Med. 2012 Oct 15;8(5):597-619. [CrossRef] PMID: [PubMed]
7. Quan SF, Budhiraja R, Javaheri S, Parthasarathy S, Berry RB. The Association Between Obstructive Sleep Apnea Defined by 3 Percent Oxygen Desaturation or Arousal Definition and Self-Reported Cardiovascular Disease in the Sleep Heart Health Study. Southwest J Pulm Crit Care. 2020;21(4):86-103. [PubMed]
8. Quan SF, Howard BV, Iber C, Kiley JP, Nieto FJ, O'Connor GT, Rapoport DM, Redline S, Robbins J, Samet JM, Wahl PW. The Sleep Heart Health Study: design, rationale, and methods. Sleep. 1997 Dec;20(12):1077-85. [PubMed]
9. Javaheri S, Barbe F, Campos-Rodriguez F, Dempsey JA, Khayat R, Javaheri S, Malhotra A, Martinez-Garcia MA, Mehra R, Pack AI, Polotsky VY, Redline S, Somers VK. Sleep Apnea: Types, Mechanisms, and Clinical Cardiovascular Consequences. J Am Coll Cardiol. 2017 Feb 21;69(7):841-858. [CrossRef] [PubMed]
10. McEvoy RD, Antic NA, Heeley E, Luo Y, Ou Q, Zhang X, Mediano O, Chen R, Drager LF, Liu Z, Chen G, Du B, McArdle N, Mukherjee S, Tripathi M, Billot L, Li Q, Lorenzi-Filho G, Barbe F, Redline S, Wang J, Arima H, Neal B, White DP, Grunstein RR, Zhong N, Anderson CS; SAVE Investigators and Coordinators. CPAP for Prevention of Cardiovascular Events in Obstructive Sleep Apnea. N Engl J Med. 2016 Sep 8;375(10):919-31. [CrossRef] [PubMed].
11. Anonymous. CPAP – Benefits and Health Risk Prevention. AASM. Sleep Education. 2015, Aug. 10. Available at: http://sleepeducation.org/essentials-in-sleep/cpap/benefits (accessed 10/18/20).

Cite as: Parish JM, Baratz D. Correct Scoring of Hypopneas in Obstructive Sleep Apnea Reduces Cardiovascular Morbidity. Southwest J Pulm Crit Care. 2020;21(4):104-7. doi: https://doi.org/10.13175/swjpcc059-20 PDF

Screening for Obstructive Sleep Apnea in the Transportation Industry—The Time is Now

Stuart F. Quan, M.D.

Division of Sleep and Circadian Disorders

Brigham and Women’s Hospital

and

Division of Sleep Medicine

Harvard Medical School

Boston, MA USA

and

Asthma and Airway Disease Research Center

University of Arizona College of Medicine,

Tucson, AZ USA

On September 29, 2016, a New Jersey Transit train failed to slow down and stop at the station in Hoboken, New Jersey. The resulting crash injured a number of passengers and killed a young mother who happened to be near the crash site. Subsequently, it was learned that the train engineer who apparently had blacked out was diagnosed as having severe obstructive sleep apnea (OSA) (1). Unfortunately, this was not an isolated incident. Over the past few years, there have been several other well-documented incidents of train, truck and bus crashes resulting from their operators falling asleep from OSA. In 2013, a Metro-North commuter train derailed outside of New York City because of excessive speed approaching a curve, the train engineer reported being “dazed” and was subsequently found to have OSA (2). Four passengers were killed and numerous others were injured. In another well-documented accident in 2013, the driver of a Greyhound bus fell asleep. The bus ran off the road, rolled on its side and injured 35 passengers. The driver had been told to get tested for OSA, but did not have the study done. A subsequent court-ordered polysomnogram showed OSA (3). In another incident in 2009, a truck-tractor semitrailer operator failed to notice slowing and stopped cars in front of him and collided with a passenger vehicle. This led to a series of rear end vehicle collisions resulting in 10 fatalities. The cause of the accident was operator fatigue related in part to OSA (4). These well-publicized incidents are only a few of the sleepiness/fatigue related accidents caused by unrecognized OSA in the transportation industry.

One of the most common symptoms attributed to OSA is daytime sleepiness which can be uncontrollable and unpredictable. Numerous studies have demonstrated that persons with OSA have an increased rate of motor vehicle accidents with up to a 4.9 fold higher risk (5). Accidents involving only a single vehicle are particularly frequent suggesting that the crashes are caused by the operators having fallen asleep. Truck drivers are at even greater risk, most likely because they are disproportionately male, middle aged and overweight, all of which are risk factors for OSA. Over a ten year span from 2004 to 2013, it has been estimated that 3,133 to 8,952 deaths and 77,000 and 220,000 serious injuries have resulted from sleepy operators of commercial motor vehicles, many of whom most likely had undiagnosed and untreated OSA (6).

Given the severe consequences of unrecognized OSA on public safety and the high prevalence of unrecognized OSA among operators of trains, buses and commercial trucks, the imperative to screen and treat these persons for OSA is high. The advisory boards to the Federal Motor Carrier Safety Administration (FMCSA) have recommended that commercial truck drivers be screened for OSA if their body mass index is > 40 kg/m², or >33 kg/m² and have 3 or more conditions or findings associated with OSA, but adoption of these recommendations has not occurred (7). More recently, the Department of Transportation, Federal Railroad Administration and the FMCSA have taken the first steps to mandate screening and treatment of rail and commercial motor vehicle operators for OSA by soliciting public comment (8). Airline pilots are already screened. However, there is substantial opposition from the trucking industry and drivers themselves, the latter because of potential job loss. However, such a screening program in one large trucking company has demonstrated a 5 fold reduction in accident rates in drivers who were adherent to CPAP treatment for OSA (5).

With the development of relatively simple to use ambulatory devices that can identify most persons with OSA, screening for OSA can be done easily and cost-effectively. In the vast majority of cases, referral to a sleep lab is not necessary. Persons diagnosed with OSA can be treated with several different modalities and are able to return to work. Employers may actually experience a reduction in their costs related to fewer accidents and improved employee health. Thus, there is no reason to delay requiring OSA screening programs for all persons working in occupations where public safety is at risk. For regulators, policy makers, and the various industries affected, the time is now. Failure to act places the responsibilities for the ensuing economic costs, injuries and deaths on your shoulders.

References

1. Marsh R, Shortell D. NJ. Train Engineer in Crash had Undiagnosed Sleep Apnea. CNN. October 17, 2016. Available at: http://www.cnn.com/2016/11/17/us/njt-engineer-sleep-apnea/ (accessed 12/2/16).
2. National Transportation Safety Board. Metro-North Railroad Derailment. October 24, 2014. Available at: http://www.ntsb.gov/investigations/accidentreports/pages/RAB1412.aspx (accessed 12/2/16).
3. Five Passengers hurt in 2013 Greyhound Bus Crash Win $6 Million Settlement Attorneys Say. WCPO Cincinnati. http://www.wcpo.com/news/local-news/hamilton-county/cincinnati/five-passengers-hurt-in-2013-greyhound-bus-crash-win-6-million-settlement-attorneys-say (accessed 12/2/16).
4. National Transportation Safety Board. Truck-Tractor Semitrailer Rear-End Collision Into Passenger Vehicles on Interstate 44. September 28, 2010. http://www.ntsb.gov/investigations/AccidentReports/Pages/HAR1002.aspx (accessed 12/2/16).
5. Tregear S, Reston J, Schoelles K, Phillips B. Obstructive sleep apnea and risk of motor vehicle crash: systematic review and meta-analysis. J Clin Sleep Med. 2009;5 (6):573–81.[PubMed]
6. Burks SV, Anderson JE, Bombyk M, et al. Nonadherence with Employer-Mandated Sleep Apnea Treatment and Increased Risk of Serious Truck Crashes. Sleep. 2016 May 1;39(5):967-75. [CrossRef] [PubMed]
7. Miller E. FMCSA Medical Review Board Issues Sleep Apnea Guidelines. Transport Topics. August 24, 2016. Available at:  http://www.ttnews.com/articles/basetemplate.aspx?storyid=42963&page=1 (accessed 12/2/16).
8. Federal Motor Carrier Safety Administration. U.S. DOT Seeks Input on Screening and Treating Commercial Motor Vehicle Drivers and Rail Workers with Obstructive Sleep Apnea. March 8, 2016. Available at: https://www.fmcsa.dot.gov/newsroom/us-dot-seeks-input-screening-and-treating-commercial-motor-vehicle-drivers-and-rail-workers (accessed 12/2/16).

Cite as: Quan SF. Screening for obstructive sleep apnea in the transportation industry—the time is now. Southwest J Pulm Crit Care. 2016;13(6):285-7. doi: https://doi.org/10.13175/swjpcc132-16 PDF

Mild Obstructive Sleep Apnea: Beyond the AHI

Joyce Lee-Iannotti MD

James M Parish MD

Division of Pulmonary Medicine (Dr Parish) Center for Sleep Medicine Department of Neurology (Dr Lee-Iannotti), Center for Sleep Medicine

Mayo Clinic Arizona

Scottsdale, Arizona

A common conundrum faced by sleep medicine practitioners is how to manage the large group of patients with mild sleep apnea. Many patients are referred for sleep evaluation, with symptoms thought to be due to obstructive sleep apnea (OSA). Often polysomnography demonstrates only mild sleep apnea, and the clinician and patient are faced with the dilemma of whether to use continuous positive airway pressure (CPAP) therapy or an oral appliance. In making this important decision the clinician incorporates the commonly used definition of mild sleep apnea as an apnea-hypopnea index of between 5 and 14 apneas or hypopneas per hour of sleep.  Moderate sleep apnea is defined as 15-29 events per hour, and severe is 30 and above events per hour. These arbitrary thresholds originated in the early 1980s when knowledge of this condition was in its infancy and little was known about the long term health effects. The definition was based on the finding of apneas, defined by the complete cessation of airflow for at least 10 seconds. The concept of hypopnea and respiratory-effort related arousal (RERA) came later and with frequently changing definitions that have been the subject of significant controversy throughout the last 30 years.  Many sleep centers include these RERA’s in the definition of respiratory disturbance index, which is incorrectly used interchangeably with AHI. While the sleep literature has demonstrated the untoward effects of moderate to severe sleep apnea, there has been considerable debate about the clinical significance of mild sleep apnea, that is, an AHI between 5 and 15.

The current paper by Quan, et al (1) is a significant contribution to the literature in sleep medicine addressing this important clinical question. This paper reports data drawn from the APPLES study, a large multi-center, well-conducted study designed to determine if CPAP therapy improves sleepiness, mood disorder, or cognitive function in patients with OSA, that has subsequently produced several important publications (2-6). As part of the study, extensive data was obtained on each of these neurocognitive parameters including the Epworth Sleepiness Scale, Stanford Sleepiness Scale, Hamilton Rating Scale for Depression, Profile of Mood States, and Sleep Apnea Quality of Life Index, all validated questionnaires used frequently in the sleep literature. In this part of the study, 199 patients with an AHI>5 but <15 were compared to 40 patients enrolled in the study, but with and AHI<5. The mean AHI was 10 per hour in the mild OSA group, and was 3 per hour in the non-OSA group.  Size of the study was statistically large enough to determine significant differences. Remarkably, there was no significant difference in any rating of sleepiness, mood, or quality of life between the two groups. This study produces an important challenge to the traditional thresholds of disease severity, and raises the question of whether mild sleep apnea based on AHI alone is a disease, and whether it truly requires treatment. Since many patients seen at sleep medicine clinics fall into this category, this is an extremely important question to address.

Several previous studies have attempted to elucidate the issue of mild sleep apnea. Barnes, et al (7) in a randomized controlled trial of CPAP in mild OSA (defined in their study as an AHI 5-30 events per hour) reported that CPAP improved self-reported symptoms of snoring, restless sleep, daytime sleepiness, and irritability, but did not improve objective measure of sleepiness (multiple sleep latency test) or any test of neurobehavioral function, quality of life, mood scores, or 24-hour blood pressure. Weaver, et al (8) reported results from the CATNAP study, a randomized, sham-CPAP controlled study of self reported sleepy patients with mild OSA (defined as AHI 5-30 events per hour) that CPAP significantly improved scores on the Functional Outcomes of Sleep Questionnaire. Both of these trials differ from the current study by defining mild OSA as an AHI up to 30 per hour, whereas the major controversy involves those patients in the AHI 5-15 range. The CATNAP study also selected patients who complained of excessive sleepiness.

The findings from this study emphasize the need to differentiate “obstructive sleep apnea” from “obstructive sleep apnea syndrome.”  Obstructive sleep apnea has been traditionally defined solely by the AHI, whereas OSA syndrome incorporates the subjective and clinical components to the diagnosis (sleepiness, mood disturbance, fatigue, etc.) An abnormal AHI in the mild range without symptoms may not warrant  treatment with CPAP, whereas an excessively sleepy patient with an AHI of 7 would require at least a trial of CPAP with close monitoring. Fatigue, although traditionally associated with mood disorders, is a common symptom in sleep medicine and may be a manifestation of untreated sleep apnea. Future studies could incorporate a fatigue scale (e.g. Fatigue Severity Score) as an adjunct to the Epworth sleepiness score to assess the importance of fatigue as a symptom of OSA.

The current study has an important limitation in that subjects were enrolled based on a referral to a sleep center for some clinical indication related to OSA, and therefore do not represent the general population. It would be possible that individuals drawn randomly from the general population would have lower scores on these tests than a group of subjects referred to a sleep center, which would result in the mild OSA group having significantly different scores on these tests than the general population. In addition the no-OSA group in this study included only 40 patients, and it is possible that a larger group of true no-OSA patients without symptoms causing referral to a sleep center would yield a slightly different result. However, if the untoward effects of mild OSA are indeed significant, it should be relatively easy to find significant abnormalities in mood, sleepiness, and quality of life, and the inability to demonstrate differences in this study group leads one to conclude that the differences, if they exist, are likely to very small.

Besides the mood and quality of life effects of sleep apnea, cardiovascular disease is known to be a significant consequence of obstructive sleep apnea (9).  Stroke, heart failure, myocardial infarction, and atrial fibrillation are known to occur more commonly in untreated OSA than in normal individuals (10). There have been several studies on the cardiovascular effects of mild sleep apnea. The Sleep Heart Health study found a small but significant increase in cardiovascular disease in mild sleep apnea (11).  In another study, Buchner et al (12) found CPAP reduced the risk of subsequent cardiovascular events in patients with mild to moderate (AHI 5-30 per hour) OSA. Therefore, the clinician must look at not only at the AHI, but the larger picture inclusive of presenting symptoms and cardiovascular and cerebrovascular risk factors when deciding on treatment.

Ultimately, this paper challenges the sleep community to look beyond the AHI and improve management algorithms for patients with mild obstructive sleep apnea, with or without symptoms. We propose that an obstructive sleep apnea score be developed, similar to the CHADS-2 score used to determine the need for anticoagulation in patients with non-valvular atrial fibrillation as a means of secondary stroke prevention (13). The “OSA score” could incorporate the AHI, the Epworth sleepiness scale, a quality of life score, a fatigue severity scale, and known cardiovascular and cerebrovascular co-morbidities. A point system could be generated to determine the need for CPAP or alternative therapies.

Hence, this study is likely to be a sentinel study in the sleep medicine literature. Further research in how to “score” patients who need treatment is needed in order to provide best value in management of sleep apnea.

References

1. Quan SF, Budhiraja R, Batool-Anwar S, Gottlieb DJ, Eichling P, Patel S, Wei Shen, Walsh JK, Kushida CA. Lack of impact of mild obstructive sleep apnea on sleepiness, mood and quality of life. Southwest J Pulm Crit Care. 2014;9(1):44-56. [CrossRef]
2. Kushida CA, Nichols DA, Quan SF, et al. The Apnea Positive Pressure Long-term Efficacy Study (APPLES): rationale, design, methods, and procedures. J Clin Sleep Med 2006;2(3):288-300. [PubMed] 
3. Quan SF, Chan CS, Dement WC, et al. The association between obstructive sleep apnea and neurocognitive performance--the Apnea Positive Pressure Long-term Efficacy Study (APPLES). Sleep 2011;34(3):303-14B. [PubMed]
4. Kushida CA, Nichols DA, Holmes TH, et al. Effects of continuous positive airway pressure on neurocognitive function in obstructive sleep apnea patients: The Apnea Positive Pressure Long-term Efficacy Study (APPLES). Sleep 2012;35(12):1593-602. [PubMed]
5. Quan SF, Budhiraja R, Clarke DP, et al. Impact of treatment with continuous positive airway pressure (CPAP) on weight in obstructive sleep apnea. J Clin Sleep Med. 2013;9(10):989-93. [PubMed]
6. Batool-Anwar S, Goodwin JL, Drescher AA, et al. Impact of CPAP on activity patterns and diet in patients with obstructive sleep apnea (OSA). J Clin Sleep Med. 2014;10(5):465-72. [PubMed] 
7. Barnes M, Houston D, Worsnop CJ, et al. A randomized controlled trial of continuous positive airway pressure in mild obstructive sleep apnea. Am J Resp Crit Care Med. 2002;165(6):773-80. [CrossRef] [PubMed] 
8. Weaver TE, Mancini C, Maislin G, et al. Continuous positive airway pressure treatment of sleepy patients with milder obstructive sleep apnea: results of the CPAP Apnea Trial North American Program (CATNAP) randomized clinical trial. Am J Respir Crit Care Med 2012;186(7):677-83. [CrossRef] [PubMed]
9. Newman AB, Nieto FJ, Guidry U, et al. Relation of sleep-disordered breathing to cardiovascular disease risk factors: the Sleep Heart Health Study. Am J Epidemiol. 2001;154(1):50-9. [CrossRef] [PubMed] 
10. Somers VK, White DP, Amin R, et al. Sleep Apnea and Cardiovascular Disease: An American Heart Association/American College of Cardiology Foundation Scientific Statement From the American Heart Association Council for High Blood Pressure Research Professional Education Committee, Council on Clinical Cardiology, Stroke Council, and Council on Cardiovascular Nursing In Collaboration With the National Heart, Lung, and Blood Institute National Center on Sleep Disorders Research (National Institutes of Health). J Am Coll Cardiol. 2008;52(8):686-717. [CrossRef] [PubMed] 
11. Shahar E, Whitney C, Redline S, et al. Sleep-disordered breathing and cardiovascular disease: cross-sectional results of the Sleep Heart Health Study. Am J Respir Crit Care Med 2001;163:19-25. [CrossRef] [PubMed] 
12. Buchner NJ, Sanner BM, Borgel J, Rump LC. Continuous Positive Airway Pressure Treatment of Mild to Moderate Obstructive Sleep Apnea Reduces Cardiovascular Risk. Am J Resp Crit Care Med. 2007;176(12):1274-80. [CrossRef] [PubMed] 
13. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA. 2001;285(22):2864-70. [CrossRef] [PubMed] 

Reference as: Lee-Iannotti J, Parish JM. Mild obstructive sleep apnea: beyond the AHI. Southwest J Pulm Crit Care. 2014;9(1):40-3. doi: http://dx.doi.org/10.13175/swjpcc099-14 PDF