COUNTERPOINT: Should Asymptomatic OSA Be Treated in Patients With Significant Cardiovascular Disease? No

Abstract

The year 2021 marked the 40th anniversary since the original description of positive airway pressure (PAP) for the treatment of OSA.1Sullivan C.E. Issa F.G. Berthon-Jones M. Eves L. Reversal of obstructive sleep apnoea by continuous positive airway pressure applied through the nares.Lancet. 1981; 1: 862-865Google Scholar In the four decades that have followed, empirical evidence on the health implications of untreated OSA has grown substantially, particularly for cardiovascular disease.2Somers V.K. White D.P. 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).Circulation. 2008; 118: 1080-1111Google Scholar,3Drager L.F. McEvoy R.D. Barbe F. Lorenzi-Filho G. Redline S. Initiative I: sleep apnea and cardiovascular disease: lessons from recent trials and need for team science.Circulation. 2017; 136: 1840-1850Google Scholar There is now irrefutable evidence that treating OSA with PAP is associated with improvements in measures of objective and subjective sleepiness, quality of life, and BP.4Giles T.L. Lasserson T.J. Smith B.J. White J. Wright J. Cates C.J. Continuous positive airways pressure for obstructive sleep apnoea in adults.Cochrane Database Syst Rev. 2006; 1: CD001106Google Scholar,5Haentjens P. Van Meerhaeghe A. Moscariello A. et al.The impact of continuous positive airway pressure on blood pressure in patients with obstructive sleep apnea syndrome: evidence from a meta-analysis of placebo-controlled randomized trials.Arch Intern Med. 2007; 167: 757-764Google Scholar Given the sizeable body of available data on the favorable effects of PAP on the reduction of BP, it is no surprise that OSA was identified as a secondary cause of hypertension in the 2003 report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.6Chobanian A.V. Bakris G.L. Black H.R. et al.Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.Hypertension. 2003; 42: 1206-1252Google Scholar In light of the unequivocal, if modest, impact of OSA treatment on BP,7Schein A.S. Kerkhoff A.C. Coronel C.C. Plentz R.D. Sbruzzi G. Continuous positive airway pressure reduces blood pressure in patients with obstructive sleep apnea; a systematic review and meta-analysis with 1000 patients.J Hypertens. 2014; 32: 1762-1773Google Scholar,8Hou H. Zhao Y. Yu W. et al.Association of obstructive sleep apnea with hypertension: a systematic review and meta-analysis.J Glob Health. 2018; 8: 010405Google Scholar a corollary expectation is that untreated OSA, through its effects on BP, is associated with increased cardiovascular risk and that PAP treatment should mitigate that risk. This corollary has been shown only to be partially true. Observational data have indeed confirmed that OSA is associated with cardiovascular disease independent of other established cardiovascular risk factors.9Sanchez-de-la-Torre M. Campos-Rodriguez F. Barbe F. Obstructive sleep apnoea and cardiovascular disease.Lancet Respir Med. 2013; 1: 61-72Google Scholar However, randomized clinical trials have failed to demonstrate a role for PAP in reducing the risk of cardiovascular events. A growing number of randomized clinical trials have been completed that have evaluated whether PAP therapy is associated with either primary or secondary prevention of cardiovascular or cerebrovascular end points or death. In patients with moderate-to-severe OSA (apnea-hypopnea index, ≥ 20 events/hr) but without excessive daytime sleepiness (Epworth Sleepiness Score, < 10), PAP therapy was not associated with a lower incidence of hypertension or cardiovascular events over a median follow-up duration of 4 years.10Barbe F. Duran-Cantolla J. Sanchez-de-la-Torre M. et al.Effect of continuous positive airway pressure on the incidence of hypertension and cardiovascular events in nonsleepy patients with obstructive sleep apnea: a randomized controlled trial.JAMA. 2012; 307: 2161-2168Google Scholar In other randomized studies, treatment of OSA with PAP after a stroke11Hsu C.Y. Vennelle M. Li H.Y. Engleman H.M. Dennis M.S. Douglas N.J. Sleep-disordered breathing after stroke: a randomised controlled trial of continuous positive airway pressure.J Neurol Neurosurg Psychiatry. 2006; 77: 1143-1149Google Scholar or in patients with coronary artery disease after revascularization12Peker Y. Glantz H. Eulenburg C. Wegscheider K. Herlitz J. Thunstrom E. Effect of positive airway pressure on cardiovascular outcomes in coronary artery disease patients with nonsleepy obstructive sleep apnea. The RICCADSA Randomized Controlled Trial.Am J Respir Crit Care Med. 2016; 194: 613-620Google Scholar has not decreased the rate of recurrent cerebrovascular events or a composite cardiovascular end point, respectively. Although each of these studies was underpowered to detect meaningful reductions in cardiovascular risk, the Sleep Apnea Cardiovascular Endpoints (SAVE) trial,13McEvoy R.D. Antic N.A. Heeley E. et al.CPAP for prevention of cardiovascular events in obstructive sleep apnea.N Engl J Med. 2016; 375: 919-931Google Scholar with 2,717 participants, had 90% power to detect a 25% reduction in the primary composite end point of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, heart failure, or a transient ischemic attack. Like earlier studies, the SAVE study also found that PAP therapy was not associated with a lower risk of this composite outcome nor in any of its individual components. The recently published ISAACC study,14Sanchez-de-la-Torre M. Sanchez-de-la-Torre A. Bertran S. et al.Effect of obstructive sleep apnoea and its treatment with continuous positive airway pressure on the prevalence of cardiovascular events in patients with acute coronary syndrome (ISAACC study): a randomised controlled trial.Lancet Respir Med. 2020; 8: 359-367Google Scholar which randomly assigned 1,264 patients with OSA and acute coronary syndrome, similarly found no significant benefit of PAP on cardiovascular events. A subsequent meta-analysis of ten randomized trials that included the SAVE study showed no association between the use of PAP and major cardiovascular events.15Yu J. Zhou Z. McEvoy R.D. et al.Association of positive airway pressure with cardiovascular events and death in adults with sleep apnea: a systematic review and meta-analysis.JAMA. 2017; 318: 156-166Google Scholar There are several plausible explanations for the failure of randomized clinical trials to confirm prior expectations that treatment of OSA would reduce cardiovascular risk. These include the possibility of residual confounding in observational studies, exclusion of symptomatic patients from the randomized trials, inadequate adherence to PAP therapy in these trials, and the possibility of adverse effects of PAP therapy. In observational studies, adjustment for adiposity generally has used BMI, although this correlates weakly with visceral adiposity, which may be more relevant to cardiovascular and metabolic disease.16Schneider H.J. Friedrich N. Klotsche J. et al.The predictive value of different measures of obesity for incident cardiovascular events and mortality.J Clin Endocrinol Metab. 2010; 95: 1777-1785Google Scholar, 17Guasch-Ferre M. Bullo M. Martinez-Gonzalez M.A. et al.Waist-to-height ratio and cardiovascular risk factors in elderly individuals at high cardiovascular risk.PLoS One. 2012; 7: e43275Google Scholar, 18Reis J.P. Allen N. Gunderson E.P. et al.Excess body mass index- and waist circumference-years and incident cardiovascular disease: the CARDIA study.Obesity (Silver Spring). 2015; 23: 879-885Google Scholar Although this may lead to an overestimate of the contribution of OSA to cardiovascular risk, the robust finding that PAP lowers BP nonetheless suggests that OSA treatment potentially could also reduce that risk. A common feature of the aforementioned clinical trials is the exclusion of patients with significant daytime sleepiness. Although as many as one-half of patients with moderate-to-severe OSA do not report excessive sleepiness, emerging evidence suggests that excess cardiovascular risk may be limited to a subset of people with a sleepy OSA phenotype. Although the available body of data from randomized clinical trials has failed to demonstrate efficacy for cardiovascular outcomes, it is well-established that PAP therapy does improve daytime sleepiness, quality of life, mood, and absenteeism from work for health-related reasons13McEvoy R.D. Antic N.A. Heeley E. et al.CPAP for prevention of cardiovascular events in obstructive sleep apnea.N Engl J Med. 2016; 375: 919-931Google Scholar; thus, PAP therapy clearly is indicated for treatment of symptomatic OSA. Proponents of PAP therapy in asymptomatic patients with cardiovascular disease and asymptomatic OSA often discount the trials conducted thus far because of methodologic limitations that include the use of different technologies to diagnose OSA, heterogeneity of disease severity, variability in follow-up duration, and most compellingly poor adherence to therapy. Indeed, some of the smaller clinical trials have reported that stratification by nightly use showed that those patients who were adherent to PAP for ≥ 4 h per night experienced a reduction in cardiovascular end points.10Barbe F. Duran-Cantolla J. Sanchez-de-la-Torre M. et al.Effect of continuous positive airway pressure on the incidence of hypertension and cardiovascular events in nonsleepy patients with obstructive sleep apnea: a randomized controlled trial.JAMA. 2012; 307: 2161-2168Google Scholar,12Peker Y. Glantz H. Eulenburg C. Wegscheider K. Herlitz J. Thunstrom E. Effect of positive airway pressure on cardiovascular outcomes in coronary artery disease patients with nonsleepy obstructive sleep apnea. The RICCADSA Randomized Controlled Trial.Am J Respir Crit Care Med. 2016; 194: 613-620Google Scholar Such analyses are likely to be biased, however, because of the well-established healthy user effect: those patients who are adherent to therapy tend to have other health-related behaviors that favorably influence the outcomes of interest.19Platt A.B. Kuna S.T. Field S.H. et al.Adherence to sleep apnea therapy and use of lipid-lowering drugs: a study of the healthy-user effect.Chest. 2010; 137: 102-108Google Scholar,20Simpson S.H. Eurich D.T. Majumdar S.R. et al.A meta-analysis of the association between adherence to drug therapy and mortality.BMJ. 2006; 333: 15Google Scholar Moreover, the larger, recent randomized trials (SAVE and ISAACC) have not found a significant reduction in cardiovascular events, even among patients with higher PAP adherence,13McEvoy R.D. Antic N.A. Heeley E. et al.CPAP for prevention of cardiovascular events in obstructive sleep apnea.N Engl J Med. 2016; 375: 919-931Google Scholar,14Sanchez-de-la-Torre M. Sanchez-de-la-Torre A. Bertran S. et al.Effect of obstructive sleep apnoea and its treatment with continuous positive airway pressure on the prevalence of cardiovascular events in patients with acute coronary syndrome (ISAACC study): a randomised controlled trial.Lancet Respir Med. 2020; 8: 359-367Google Scholar but did show that there was a reduction in cerebrovascular events. The latter finding greatly highlights the incredible relevance of PAP adherence in future clinical trials. The argument is also made that, given the consistency of findings from cohort studies on the association between OSA and incident cardiovascular disease, denying any patient with OSA and prevalent cardiovascular disease a seemingly benign therapy would be unethical, even if the patient was asymptomatic. However, this logic is flawed not only in its elevation of observational over experimental data but also in its assumption that PAP therapy is entirely benign. The medical literature has an abundance of examples in which observational data suggest that an intervention has favorable effects, but divergent findings are uncovered when the same intervention is examined in the setting of a randomized trial. A paradigm example is the use of hormone replacement therapy (HRT) in menopause. Through the 1990s, observational studies showed that HRT had benefits not only regarding the treatment of menopausal symptoms, but also in the prevention of chronic disease.21Stampfer M.J. Colditz G.A. Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiologic evidence.Prev Med. 1991; 20: 47-63Google Scholar, 22Grady D. Rubin S.M. Petitti D.B. et al.Hormone therapy to prevent disease and prolong life in postmenopausal women.Ann Intern Med. 1992; 117: 1016-1037Google Scholar, 23Grodstein F. Stampfer M.J. Colditz G.A. et al.Postmenopausal hormone therapy and mortality.N Engl J Med. 1997; 336: 1769-1775Google Scholar, 24Yaffe K. Sawaya G. Lieberburg I. Grady D. Estrogen therapy in postmenopausal women: effects on cognitive function and dementia.JAMA. 1998; 279: 688-695Google Scholar As a consequence, HRT became common practice in postmenopausal women and was recommended in American College of Physicians guidelines for both primary and secondary prevention of cardiovascular disease.22Grady D. Rubin S.M. Petitti D.B. et al.Hormone therapy to prevent disease and prolong life in postmenopausal women.Ann Intern Med. 1992; 117: 1016-1037Google Scholar,25American College of PhysiciansGuidelines for counseling postmenopausal women about preventive hormone therapy.Ann Intern Med. 1992; 117: 1038-1041Google Scholar However, in the late 1990s, the Women’s Health Initiative was launched to examine the use of a randomized design: the effects of HRT on cardiovascular disease, osteoporosis, cancer, and death. The trial was stopped prematurely when it was found that HRT was associated with increased incidence of coronary heart disease and breast cancer, albeit with a concomitant reduction in osteoporotic fractures and colorectal cancer.26Rossouw J.E. Anderson G.L. Prentice R.L. et al.Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial.JAMA. 2002; 288: 321-333Google Scholar Although the results of the Women’s Health Initiative have been a topic of much controversy and subsequent analyses and follow-up studies have shown benefits of alternative formulations of HRT in specific age groups,27Cagnacci A. Venier M. The controversial history of hormone replacement therapy.Medicina (Kaunas). 2019; 55Google Scholar this example illustrates that observational and interventional studies can, at times, provide opposing views. It also suggests the importance of ongoing research to identify subgroups of patients with OSA who might benefit from PAP therapy, despite a lack of symptoms. Another example of divergent conclusions between observational studies and randomized trials germane to the current discussion is the use of adaptive servo ventilation (ASV) for treatment of Cheyne-Stokes respiration in patients with heart failure with reduced ejection fraction. Initial data on the use of ASV, based predominantly on studies that used observational designs and small study samples, showed modest improvements in intermediate outcomes such as the apnea-hypopnea index and left ventricular ejection fraction.28Aurora R.N. Chowdhuri S. Ramar K. et al.The treatment of central sleep apnea syndromes in adults: practice parameters with an evidence-based literature review and meta-analyses.Sleep. 2012; 35: 17-40Google Scholar Even with such limited data, the American Academy of Sleep Medicine practice parameters recommended the use of ASV for treatment of central sleep apnea related to chronic heart failure.28Aurora R.N. Chowdhuri S. Ramar K. et al.The treatment of central sleep apnea syndromes in adults: practice parameters with an evidence-based literature review and meta-analyses.Sleep. 2012; 35: 17-40Google Scholar These recommendations were reversed after results of the Adaptive Servo-Ventilation for Central Sleep Apnea in Systolic Heart Failure (SERVE-HF) trial29Cowie M.R. Woehrle H. Wegscheider K. et al.Adaptive servo-ventilation for central sleep apnea in systolic heart failure.N Engl J Med. 2015; 373: 1095-1105Google Scholar showed that, in patients with a left ventricular ejection fraction of ≤45%, there was no difference between groups in a composite end point of death from any cause, lifesaving cardiovascular intervention, or unplanned hospitalizations. Surprisingly, ASV was associated with an unexpected 34% increase in all-cause and cardiovascular death. Although the underlying reasons for adverse outcomes with ASV remain controversial and the target sample of the SERVE-HF study included patients with central sleep apnea, it should serve as a caution against the assumption of no harm from any particular therapy such as ASV. Based on the foregoing discussion, should we conclude that every therapeutic intervention requires a randomized clinical trial for assessment of efficacy? The well-touted example that there are no controlled trials on whether parachutes prevent major trauma does not lead to the conclusion that parachutes should not be used as a preventive measure to jump out of an aircraft,30Smith G.C. Pell J.P. Parachute use to prevent death and major trauma related to gravitational challenge: systematic review of randomised controlled trials.BMJ. 2003; 327: 1459-1461Google Scholar nor does a lack of randomized clinical trials reasonably lead to the conclusion that massive transfusion should not be used in the setting of life-threating massive hemorrhage. Few situations in medicine are so starkly obvious, however; although PAP therapy is likely benign, it is important to remember the directive to “above all, do no harm.” As applied to the individual patient, the cost of the PAP device and the supplies and electricity required to operate it and the adverse impact on quality of life that can result when an asymptomatic person attempts to sleep with a PAP machine make it unclear that the risk-benefit assessment favors PAP use. Moreover, the principle of “do no harm” should also apply to society at large. Considering the extraordinarily high prevalence of asymptomatic OSA,31Gottlieb D.J. Punjabi N.M. Diagnosis and management of obstructive sleep apnea: a review.JAMA. 2020; 323: 1389-1400Google Scholar the short- and long-term impact of prescribing interventions that may not benefit patients and, in fact, could harm health care systems by diverting limited resources to therapies that are not efficacious are not trivial. So, what is a practicing clinician to do when faced with an asymptomatic patient with moderate-to-severe OSA and prevalent cardiovascular disease who is not being treated with PAP or is on therapy but finds no benefit? The simple answer is that the patient needs to be engaged in a shared decision-making process with an individualized approach. Perhaps a reassessment of the patient’s clinical history uncovers unrecognized symptoms of sleepiness, fatigue, or even depression that would motivate a trial of therapy. If there is evidence of hypertension that is not controlled optimally, it too could support the recommendation of therapy in the absence of symptoms. Even in these scenarios, patients need to deliberate the pros and cons of starting therapy and its implications. However, absent any of the evidence-based indications for PAP therapy, its use in patients with asymptomatic OSA for the primary or secondary prevention of cardiovascular disease is not justified empirically, for now. Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript. POINT: Should Asymptomatic OSA Be Treated in Patients With Significant Cardiovascular Disease? YesCHESTVol. 161Issue 3PreviewOSA is estimated to afflict >1 billion individuals worldwide1 and is associated with the development of adverse cardiovascular outcomes and increased mortality rates, based upon meta-analyses of thousands of individuals.2 Clinical trials designed to investigate impact of positive airway pressure (PAP) treatment of OSA on various outcomes, however, have been challenging to interpret, given inherent limitations that include suboptimal treatment adherence. The third edition of the International Classification of Sleep Disorders by the American Academy of Sleep Medicine recommends CPAP treatment for the following conditions: (1) apnea hypopnea index > 5 with one or more symptoms (eg, sleepiness, fatigue, insomnia, snoring) or an associated medical or psychiatric disorder (eg, hypertension, coronary artery disease, atrial fibrillation) or (2) apnea hypopnea index > 15, irrespective of symptoms or associated conditions. Full-Text PDF