pii: sp-00145-15
http://dx.doi.org/10.5665/sleep.4644
EDITORIAL
Obstructive Sleep Apnea: How Much Is Too Much? Commentary on Hla et al. Coronary heart disease incidence in sleep disordered breathing: the Wisconsin Sleep Cohort Study. SLEEP 2015;38:677–684. Daniel J. Gottlieb, MD, MPH VA Boston Healthcare System, Brigham & Women’s Hospital, and Harvard Medical School, Boston, MA
Obstructive sleep apnea (OSA) is an extremely common chronic medical condition, with an estimated U.S. prevalence of 17% of women and 34% of men age 30–70 years.1 The potential public health impact, as well as the potential cost of OSA treatment, is therefore extraordinary. While there is a clear indication for treatment of OSA when associated with excessive sleepiness, fewer than half of patients with OSA identified through general population screening report excessive sleepiness.1,2 In the many asymptomatic or minimally symptomatic patients, a possible rationale for treatment is to reduce cardiovascular risk. The report by Hla et al. in the current issue of SLEEP 3 adds evidence from the Wisconsin Sleep Cohort, the pre-eminent population-based epidemiologic study of sleep apnea, for an association between OSA and incident coronary heart disease (CHD) and heart failure. Although not initially designed to examine, nor powered to detect, such an association, the detailed sleep evaluation and careful long-term follow-up of the cohort has allowed important contributions to a growing literature on the cardiovascular consequences of OSA. While the findings presented in their paper are largely supportive of what has been previously reported from both clinic- and communitybased studies, several facets of the study deserve attention. One of their observations is that the association with increased cardiovascular risk was driven almost entirely by a large effect in women. This appears to be opposite to the finding in the community-based Sleep Heart Health Study, where the association of OSA with CHD and heart failure was seen exclusively in men.4 While the sex difference was not statistically significant in the report of Hla et al.,3 the lack of association in men is surprising, given the much higher prevalence of OSA and incidence of CHD in men than in women, which should have provided greater power to detect an effect in men. While most clinic-based studies of this association have been in predominantly male cohorts,5–8 recent clinic-based studies demonstrating significant associations in women,9 together with the findings of Hla et al.,3 suggest no clear sex difference in the OSA-cardiovascular disease relationship. A second and potentially more important feature of the Hla study is the unusual choice of referent group: individuals with apnea-hypopnea index (AHI) precisely equal to zero. It is Submitted for publication March, 2015 Accepted for publication March, 2015 Address correspondence to: Daniel J. Gottlieb, MD, FAASM, Division of Sleep Medicine, Brigham and Women’s Hospital, 221 Longwood Avenue, BLI 225E, Boston, MA 02115; Tel: (857) 203-6375; Fax: (857) 203-5670; Email: [email protected] SLEEP, Vol. 38, No. 5, 2015
hardly the case that OSA severity was “categorized according to widely used cut points in the literature and clinical practice.”3 On the contrary, clinical guidelines from the American Academy of Sleep Medicine10 consider AHI < 5 to be normal, and it is nearly universal practice in the literature to use a referent group of AHI < 5. The choice of referent group has important implications for interpreting the results of this study, as the group with “minimal” OSA, defined as AHI > 0 to < 5, had an adjusted hazard ratio for CHD or heart failure of 1.53. Including in the referent group these individuals, who comprise more than half of the study sample, would have substantially reduced the estimated hazard ratios for those with AHI of 5 or more, to levels that would likely have been nonsignificant. Are the 19% of individuals with AHI of zero an appropriate reference group? Typical of individuals without OSA, they are younger, thinner, and more likely to be women than the overall sample. They also obtain more exercise, have higher HDL cholesterol, and are less likely to drink heavily or have diabetes or hypertension. Their usual sleep duration is not reported. Might they be an ultra-healthy group in whom an AHI of zero is, in the words of the authors, a proxy for unmeasured confounders? These could be confounders that we routinely consider, such as adiposity or glucose homeostasis, for which the covariates BMI and diagnosed diabetes are certainly imperfect measures. They could also be confounders that we rarely include in our models because they are difficult to measure, such as stress, which may cause lighter sleep11 and thereby predispose to a mildly elevated AHI, due to the greater susceptibility of the airway to collapse at the wake-sleep transition.12 A referent group of AHI = 0 might thereby falsely exaggerate OSA-associated cardiovascular risk. On the other hand, it is important to recognize that an AHI of 5 events per hour is a threshold more of convenience than of science. It is plausible that any amount of sleep disordered breathing increases cardiovascular risk. This is analogous to the effect of higher blood pressure, which even within the “normal” range is associated with greater cardiovascular risk.13 The report from Hla et al.,3 along with the previous publication from this cohort suggesting that AHI > 0 to < 5 is associated with increased risk of incident hypertension,14 should cause us to re-examine the threshold OSA severity associated with increased cardiovascular risk. If the risk estimates for this group are accurate and the association is causal, this would have the extraordinary implication that one-fifth of all cases of CHD and heart failure in this sample are attributable to such “minimal” OSA, a larger population attributable fraction than that of mild, moderate and severe OSA combined.15 Managing this risk would require a combination of population 659
Editorial—Gottlieb
health strategies to reduce OSA prevalence, the development of tools to better identify those individuals with “minimal” OSA whose cardiovascular risk is in fact elevated, and the development of therapies to reduce OSA-related cardiovascular risk. These therapies might not require treatment of OSA per se, but rather target the pathways that lead from OSA to cardiovascular disease (e.g., pharmacotherapy to reduce sympathetic nervous system activity, inflammation or oxidative stress). But these considerations put the cart before the horse. To date, there is considerable evidence from observational studies for an association between OSA and cardiovascular disease. The causal nature of this association remains to be established through clinical trials demonstrating that treatment of OSA can not only modestly reduce blood pressure, as has now been amply demonstrated,16–18 but can also reduce the risk of major adverse cardiovascular events. Fortunately, several such trials are in progress, the largest of which is the Sleep Apnea Cardiovascular Endpoints (SAVE) study,19 which has randomized over 2,700 patients to CPAP or usual care and is scheduled to complete follow-up later this year. Should such studies demonstrate a cardiovascular benefit to treatment of OSA, it will be incumbent upon the sleep research community to more clearly identify the population at risk and develop effective strategies to mitigate that risk.
4. Gottlieb DJ, Yenokyan G, Newman AB, et al. Prospective study of obstructive sleep apnea and incident coronary heart disease and heart failure: the sleep heart health study. Circulation 2010;122:352–60. 5. Mooe T, Franklin KA, Holmstrom K, Rabben T, Wiklund U. Sleepdisordered breathing and coronary artery disease: long-term prognosis. Am J Respir Crit Care Med 2001;164:1910–3. 6. Peker Y, Carlson J, Hedner J. Increased incidence of coronary artery disease in sleep apnoea: a long-term follow-up. Eur Respir J 2006;28:596–602. 7. Marin JM, Carrizo SJ, Vicente E, Agusti AG. Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet 2005;365:1046–53. 8. Garcia-Rio F, Alonso-Fernández A, Armada E, et al. CPAP effect on recurrent episodes in patients with sleep apnea and myocardial infarction. Int J Cardiol 2013;168:1328–35. 9. Campos-Rodriguez F, Martinez-Garcia MA, Reyes-Nunez N, et al. Role of sleep apnea and CPAP therapy in the incidence of stroke or coronary heart disease in women. Am J Respir Crit Care Med 2014;189:1544–50. 10. Epstein LJ, Kristo D, Strollo PJ, et al. Clinical guideline for the evaluation, management and long-term care of obstructive sleep apnea in adults. J Clin Sleep Med 2009;5:263–76. 11. Åkerstedt T, Lekander M, Petersén H, Kecklund G, Axelsson J. Sleep polysomnography and reported stress across 6 weeks. Ind Health 2014;52:36–42. 12. Jordan AS, White DP. Pharyngeal motor control and the pathogenesis of obstructive sleep apnea. Respir Physiol Neurobiol 2008;160:1–7. 13. Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. BMJ 2009;338:b1665. 14. Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 2000;342:1378–84. 15. Miettinen O. Proportion of disease caused or prevented by a given exposure, trait, or intervention. Am J Epidemiol 1974;99:325–32. 16. Durán-Cantolla J, Aizpuru F, Montserrat JM, et al. Continuous positive airway pressure as treatment for systemic hypertension in people with obstructive sleep apnoea: randomised controlled trial. BMJ 2010;341:c5991. 17. Martínez-García M-A, Capote F, Campos-Rodríguez F, et al. Effect of CPAP on blood pressure in patients with obstructive sleep apnea and resistant hypertension: the HIPARCO randomized clinical trial. JAMA 2013;310:2407–15. 18. Gottlieb DJ, Punjabi NM, Mehra R, et al. CPAP versus oxygen in obstructive sleep apnea. N Engl J Med 2014;370:2276–85. 19. Antic NA, Heeley E, Anderson CS, et al. The sleep apnea cardiovascular endpoints (SAVE) trial: rationale, ethics, design, and progress. Sleep 2014 Nov 24. [Epub ahead of print].
CITATION Gottlieb DJ. Obstructive sleep apnea: how much is too much? SLEEP 2015;38(5):659–660. DISCLOSURE STATEMENT Dr. Gottlieb has indicated no financial conflicts of interest. 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;177:1006–14. 2. Kapur VK, Baldwin CM, Resnick HE, Gottlieb DJ, Nieto FJ. Sleepiness in patients with moderate to severe sleep-disordered breathing. Sleep 2005;28:472–7. 3. Hla KM, Young T, Hagen EW, et al. Coronary heart disease incidence in sleep-disordered breathing: the Wisconsin Sleep Cohort Study. Sleep 2015;38:677–84.
SLEEP, Vol. 38, No. 5, 2015
660
Editorial—Gottlieb
http://dx.doi.org/10.5665/sleep.4644
EDITORIAL
Obstructive Sleep Apnea: How Much Is Too Much? Commentary on Hla et al. Coronary heart disease incidence in sleep disordered breathing: the Wisconsin Sleep Cohort Study. SLEEP 2015;38:677–684. Daniel J. Gottlieb, MD, MPH VA Boston Healthcare System, Brigham & Women’s Hospital, and Harvard Medical School, Boston, MA
Obstructive sleep apnea (OSA) is an extremely common chronic medical condition, with an estimated U.S. prevalence of 17% of women and 34% of men age 30–70 years.1 The potential public health impact, as well as the potential cost of OSA treatment, is therefore extraordinary. While there is a clear indication for treatment of OSA when associated with excessive sleepiness, fewer than half of patients with OSA identified through general population screening report excessive sleepiness.1,2 In the many asymptomatic or minimally symptomatic patients, a possible rationale for treatment is to reduce cardiovascular risk. The report by Hla et al. in the current issue of SLEEP 3 adds evidence from the Wisconsin Sleep Cohort, the pre-eminent population-based epidemiologic study of sleep apnea, for an association between OSA and incident coronary heart disease (CHD) and heart failure. Although not initially designed to examine, nor powered to detect, such an association, the detailed sleep evaluation and careful long-term follow-up of the cohort has allowed important contributions to a growing literature on the cardiovascular consequences of OSA. While the findings presented in their paper are largely supportive of what has been previously reported from both clinic- and communitybased studies, several facets of the study deserve attention. One of their observations is that the association with increased cardiovascular risk was driven almost entirely by a large effect in women. This appears to be opposite to the finding in the community-based Sleep Heart Health Study, where the association of OSA with CHD and heart failure was seen exclusively in men.4 While the sex difference was not statistically significant in the report of Hla et al.,3 the lack of association in men is surprising, given the much higher prevalence of OSA and incidence of CHD in men than in women, which should have provided greater power to detect an effect in men. While most clinic-based studies of this association have been in predominantly male cohorts,5–8 recent clinic-based studies demonstrating significant associations in women,9 together with the findings of Hla et al.,3 suggest no clear sex difference in the OSA-cardiovascular disease relationship. A second and potentially more important feature of the Hla study is the unusual choice of referent group: individuals with apnea-hypopnea index (AHI) precisely equal to zero. It is Submitted for publication March, 2015 Accepted for publication March, 2015 Address correspondence to: Daniel J. Gottlieb, MD, FAASM, Division of Sleep Medicine, Brigham and Women’s Hospital, 221 Longwood Avenue, BLI 225E, Boston, MA 02115; Tel: (857) 203-6375; Fax: (857) 203-5670; Email: [email protected] SLEEP, Vol. 38, No. 5, 2015
hardly the case that OSA severity was “categorized according to widely used cut points in the literature and clinical practice.”3 On the contrary, clinical guidelines from the American Academy of Sleep Medicine10 consider AHI < 5 to be normal, and it is nearly universal practice in the literature to use a referent group of AHI < 5. The choice of referent group has important implications for interpreting the results of this study, as the group with “minimal” OSA, defined as AHI > 0 to < 5, had an adjusted hazard ratio for CHD or heart failure of 1.53. Including in the referent group these individuals, who comprise more than half of the study sample, would have substantially reduced the estimated hazard ratios for those with AHI of 5 or more, to levels that would likely have been nonsignificant. Are the 19% of individuals with AHI of zero an appropriate reference group? Typical of individuals without OSA, they are younger, thinner, and more likely to be women than the overall sample. They also obtain more exercise, have higher HDL cholesterol, and are less likely to drink heavily or have diabetes or hypertension. Their usual sleep duration is not reported. Might they be an ultra-healthy group in whom an AHI of zero is, in the words of the authors, a proxy for unmeasured confounders? These could be confounders that we routinely consider, such as adiposity or glucose homeostasis, for which the covariates BMI and diagnosed diabetes are certainly imperfect measures. They could also be confounders that we rarely include in our models because they are difficult to measure, such as stress, which may cause lighter sleep11 and thereby predispose to a mildly elevated AHI, due to the greater susceptibility of the airway to collapse at the wake-sleep transition.12 A referent group of AHI = 0 might thereby falsely exaggerate OSA-associated cardiovascular risk. On the other hand, it is important to recognize that an AHI of 5 events per hour is a threshold more of convenience than of science. It is plausible that any amount of sleep disordered breathing increases cardiovascular risk. This is analogous to the effect of higher blood pressure, which even within the “normal” range is associated with greater cardiovascular risk.13 The report from Hla et al.,3 along with the previous publication from this cohort suggesting that AHI > 0 to < 5 is associated with increased risk of incident hypertension,14 should cause us to re-examine the threshold OSA severity associated with increased cardiovascular risk. If the risk estimates for this group are accurate and the association is causal, this would have the extraordinary implication that one-fifth of all cases of CHD and heart failure in this sample are attributable to such “minimal” OSA, a larger population attributable fraction than that of mild, moderate and severe OSA combined.15 Managing this risk would require a combination of population 659
Editorial—Gottlieb
health strategies to reduce OSA prevalence, the development of tools to better identify those individuals with “minimal” OSA whose cardiovascular risk is in fact elevated, and the development of therapies to reduce OSA-related cardiovascular risk. These therapies might not require treatment of OSA per se, but rather target the pathways that lead from OSA to cardiovascular disease (e.g., pharmacotherapy to reduce sympathetic nervous system activity, inflammation or oxidative stress). But these considerations put the cart before the horse. To date, there is considerable evidence from observational studies for an association between OSA and cardiovascular disease. The causal nature of this association remains to be established through clinical trials demonstrating that treatment of OSA can not only modestly reduce blood pressure, as has now been amply demonstrated,16–18 but can also reduce the risk of major adverse cardiovascular events. Fortunately, several such trials are in progress, the largest of which is the Sleep Apnea Cardiovascular Endpoints (SAVE) study,19 which has randomized over 2,700 patients to CPAP or usual care and is scheduled to complete follow-up later this year. Should such studies demonstrate a cardiovascular benefit to treatment of OSA, it will be incumbent upon the sleep research community to more clearly identify the population at risk and develop effective strategies to mitigate that risk.
4. Gottlieb DJ, Yenokyan G, Newman AB, et al. Prospective study of obstructive sleep apnea and incident coronary heart disease and heart failure: the sleep heart health study. Circulation 2010;122:352–60. 5. Mooe T, Franklin KA, Holmstrom K, Rabben T, Wiklund U. Sleepdisordered breathing and coronary artery disease: long-term prognosis. Am J Respir Crit Care Med 2001;164:1910–3. 6. Peker Y, Carlson J, Hedner J. Increased incidence of coronary artery disease in sleep apnoea: a long-term follow-up. Eur Respir J 2006;28:596–602. 7. Marin JM, Carrizo SJ, Vicente E, Agusti AG. Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet 2005;365:1046–53. 8. Garcia-Rio F, Alonso-Fernández A, Armada E, et al. CPAP effect on recurrent episodes in patients with sleep apnea and myocardial infarction. Int J Cardiol 2013;168:1328–35. 9. Campos-Rodriguez F, Martinez-Garcia MA, Reyes-Nunez N, et al. Role of sleep apnea and CPAP therapy in the incidence of stroke or coronary heart disease in women. Am J Respir Crit Care Med 2014;189:1544–50. 10. Epstein LJ, Kristo D, Strollo PJ, et al. Clinical guideline for the evaluation, management and long-term care of obstructive sleep apnea in adults. J Clin Sleep Med 2009;5:263–76. 11. Åkerstedt T, Lekander M, Petersén H, Kecklund G, Axelsson J. Sleep polysomnography and reported stress across 6 weeks. Ind Health 2014;52:36–42. 12. Jordan AS, White DP. Pharyngeal motor control and the pathogenesis of obstructive sleep apnea. Respir Physiol Neurobiol 2008;160:1–7. 13. Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. BMJ 2009;338:b1665. 14. Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 2000;342:1378–84. 15. Miettinen O. Proportion of disease caused or prevented by a given exposure, trait, or intervention. Am J Epidemiol 1974;99:325–32. 16. Durán-Cantolla J, Aizpuru F, Montserrat JM, et al. Continuous positive airway pressure as treatment for systemic hypertension in people with obstructive sleep apnoea: randomised controlled trial. BMJ 2010;341:c5991. 17. Martínez-García M-A, Capote F, Campos-Rodríguez F, et al. Effect of CPAP on blood pressure in patients with obstructive sleep apnea and resistant hypertension: the HIPARCO randomized clinical trial. JAMA 2013;310:2407–15. 18. Gottlieb DJ, Punjabi NM, Mehra R, et al. CPAP versus oxygen in obstructive sleep apnea. N Engl J Med 2014;370:2276–85. 19. Antic NA, Heeley E, Anderson CS, et al. The sleep apnea cardiovascular endpoints (SAVE) trial: rationale, ethics, design, and progress. Sleep 2014 Nov 24. [Epub ahead of print].
CITATION Gottlieb DJ. Obstructive sleep apnea: how much is too much? SLEEP 2015;38(5):659–660. DISCLOSURE STATEMENT Dr. Gottlieb has indicated no financial conflicts of interest. 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;177:1006–14. 2. Kapur VK, Baldwin CM, Resnick HE, Gottlieb DJ, Nieto FJ. Sleepiness in patients with moderate to severe sleep-disordered breathing. Sleep 2005;28:472–7. 3. Hla KM, Young T, Hagen EW, et al. Coronary heart disease incidence in sleep-disordered breathing: the Wisconsin Sleep Cohort Study. Sleep 2015;38:677–84.
SLEEP, Vol. 38, No. 5, 2015
660
Editorial—Gottlieb
