CPAP Treatment and Cardiovascular Prevention
2019; Elsevier BV; Volume: 156; Issue: 3 Linguagem: Inglês
10.1016/j.chest.2019.04.092
ISSN1931-3543
AutoresShahrokh Javaheri, Miguel Ángel Martínez‐García, Francisco Campos‐Rodríguez,
Tópico(s)Gastroesophageal reflux and treatments
ResumoNumerous studies have demonstrated the pathophysiologic mechanisms mediating adverse cardiovascular and cerebrovascular (CV) consequences of OSA. Further, large observational studies have shown that CPAP therapy reduces the CV burden of OSA.1Javaheri S. Barbe F. Campos-Rodriguez F. et al.Sleep apnea: types, mechanisms, and clinical cardiovascular consequences.J Am Coll Cardiol. 2017; 69: 841-858Crossref PubMed Scopus (598) Google Scholar Yet, randomized controlled trials (RCTs) have failed to demonstrate the treatment efficacy of CPAP.2McEvoy 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: 919-931Crossref PubMed Scopus (1180) Google Scholar, 3Barbé F. Durán-Cantolla J. Sánchez 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: 2161-2168Crossref PubMed Scopus (589) Google Scholar, 4Peker Y. Glantz H. Eulenburg C. et al.Effect of positive airway pressure on cardiovascular outcomes in coronary artery disease patients with non-sleepy obstructive sleep apnea: the RICCADSA randomized controlled trial.Am J Respir Crit Care Med. 2016; 194: 613-620Crossref PubMed Scopus (367) Google Scholar In the largest trial (SAVE [Sleep Apnea Cardiovascular Endpoints]),2McEvoy 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: 919-931Crossref PubMed Scopus (1180) Google Scholar 2,687 patients with OSA and established CV disorders were randomized to CPAP or usual care. After a mean follow-up of 3.7 years and a mean CPAP use of 3.3 h/d, the intention-to-treat analysis showed lack of benefit of CPAP therapy for the composite end point (death from any CV cause, myocardial infarction, stroke, hospitalization for heart failure, unstable angina, or transient ischemic attack [TIA]). Similar results were obtained from a meta-analysis.5Yu 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: 156-166Crossref PubMed Scopus (0) Google Scholar These RCTs and meta-analysis,2McEvoy 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: 919-931Crossref PubMed Scopus (1180) Google Scholar, 3Barbé F. Durán-Cantolla J. Sánchez 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: 2161-2168Crossref PubMed Scopus (589) Google Scholar, 4Peker Y. Glantz H. Eulenburg C. et al.Effect of positive airway pressure on cardiovascular outcomes in coronary artery disease patients with non-sleepy obstructive sleep apnea: the RICCADSA randomized controlled trial.Am J Respir Crit Care Med. 2016; 194: 613-620Crossref PubMed Scopus (367) Google Scholar, 5Yu 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: 156-166Crossref PubMed Scopus (0) Google Scholar however, have had a number of pitfalls.6Martinez-Garcia M.A. Campos-Rodriguez F. Javaheri S. et al.Pro: continuous positive airway pressure and cardiovascular prevention.Eur Respir J. 2018; 51: 1702400Crossref PubMed Scopus (21) Google Scholar Based on what we have learned from these studies, the objective of this commentary is to provide suggestions regarding the challenges in design and implementation for future well-thought-out RCTs to address whether CPAP therapy can reduce OSA-associated CV risks. Previous RCTs2McEvoy 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: 919-931Crossref PubMed Scopus (1180) Google Scholar, 3Barbé F. Durán-Cantolla J. Sánchez 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: 2161-2168Crossref PubMed Scopus (589) Google Scholar, 4Peker Y. Glantz H. Eulenburg C. et al.Effect of positive airway pressure on cardiovascular outcomes in coronary artery disease patients with non-sleepy obstructive sleep apnea: the RICCADSA randomized controlled trial.Am J Respir Crit Care Med. 2016; 194: 613-620Crossref PubMed Scopus (367) Google Scholar have enrolled from CV clinics patients with OSA with a wide range of severities, mainly based on the apnea-hypopnea index (AHI) metric. This approach has some advantages, especially that patients can be randomized to a nontreatment group for a long time, because they are usually less symptomatic and have a high probability of incident CV outcomes, significantly reducing the sample size. However, this approach has a series of limitations: the results cannot be extrapolated to most patients with OSA referred to sleep clinics, because of different characteristics and CV risk factors. Specifically, most participants in the trials were asymptomatic and not seeking medical advice for sleep complaints. Therefore, it is possible that nonsleepy participants were most concerned with their CV disease rather than OSA, potentially leading to poor CPAP adherence. In contrast, patients referred to sleep units for sleep symptoms, the typical patients with OSA seen in clinical practice, might be more adherent to CPAP, which improves OSA-related symptoms including excessive daytime sleepiness (EDS). We emphasize that in OSA there may be biopathophysiologic mechanisms linking EDS to inflammation, due to upregulation of somnogenic cytokines,7Vgontzas A.N. Papanicolaou D.A. Bixler E.O. Kales A. Tyson K. Chrousos G.P. Elevation of plasma cytokines in disorders of excessive daytime sleepiness: role of sleep disturbance and obesity.J Clin Endocrinol Metab. 1997; 82: 1313-1316Crossref PubMed Google Scholar, 8Kapsimalis F. Basta M. Varouchakis G. Gourgoulianis K. Vgontzas A. Kryger M. Cytokines and pathological sleep.Sleep Med. 2008; 9: 603-614Crossref PubMed Scopus (106) Google Scholar and cytokines may play an important role in the pathogenesis of OSA and related downstream CV consequences.1Javaheri S. Barbe F. Campos-Rodriguez F. et al.Sleep apnea: types, mechanisms, and clinical cardiovascular consequences.J Am Coll Cardiol. 2017; 69: 841-858Crossref PubMed Scopus (598) Google Scholar, 7Vgontzas A.N. Papanicolaou D.A. Bixler E.O. Kales A. Tyson K. Chrousos G.P. Elevation of plasma cytokines in disorders of excessive daytime sleepiness: role of sleep disturbance and obesity.J Clin Endocrinol Metab. 1997; 82: 1313-1316Crossref PubMed Google Scholar, 8Kapsimalis F. Basta M. Varouchakis G. Gourgoulianis K. Vgontzas A. Kryger M. Cytokines and pathological sleep.Sleep Med. 2008; 9: 603-614Crossref PubMed Scopus (106) Google Scholar Patients with OSA with subjective9Kapur V.K. Resnick H.E. Gottlieb D.J. Sleep Heart Health Study GroupSleep disordered breathing and hypertension: does self-reported sleepiness modify the association?.Sleep. 2008; 31: 1127-1132PubMed Google Scholar, 10Lloberes P. Lozano L. Sampol G. et al.Obstructive sleep apnoea and 24-h blood pressure in patients with resistant hypertension.Sleep Res. 2010; 19: 597-602Crossref PubMed Scopus (44) Google Scholar or objective11Ren R. Li Y. Zhang J. et al.Obstructive sleep apnea with objective daytime sleepiness is associated with hypertension.Hypertension. 2016; 68: 1264-1270Crossref PubMed Scopus (37) Google Scholar EDS have a higher prevalence of hypertension than those without EDS, and changes in EDS are associated with blood pressure lowering of CPAP,12Robinson G.V. Langford B.A. Smith D.M. Stradling J.R. Predictors of blood pressure fall with continuous positive airway pressure (CPAP) treatment of obstructive sleep apnoea (OSA).Thorax. 2008; 63: 855-859Crossref PubMed Scopus (53) Google Scholar which is in contrast to nonsleepy patients with OSA.13Robinson G.V. Smith D.M. Langford B.A. Davies R.J.O. Stradling J.R. Continuous positive airway pressure does not reduce blood pressure in nonsleepy hypertensive OSA patients.Eur Respir J. 2006; 27: 1229-1235Crossref PubMed Scopus (291) Google Scholar Importantly, insulin resistance is significantly related to EDS, determined both objectively and subjectively,14Barcelo A. Barbe F. de la Pen M. et al.Insulin resistance and daytime sleepiness in patients with sleep apnoea.Thorax. 2008; 63: 946-950Crossref PubMed Scopus (146) Google Scholar and patients with EDS who are recovering from myocardial infarction have higher rates of major adverse CV events and reinfarction than those without EDS.15Xie J. Sert Kuniyoshi F.H. Covassin N. et al.Excessive daytime sleepiness independently predicts increased cardiovascular risk after myocardial infarction.J Am Heart Assoc. 2018; 7: e007221Crossref PubMed Scopus (51) Google Scholar Perhaps not surprisingly, EDS has been linked to CV mortality.16Empana J.P. Dauvilliers Y. Dartigues J.F. et al.Excessive daytime sleepiness is an independent risk indicator for cardiovascular mortality in community-dwelling elderly: the Three City Study.Stroke. 2009; 40: 1219-1224Crossref PubMed Scopus (135) Google Scholar, 17Newman A.B. Spiekerman C.F. Enright P. et al.Cardiovascular Health Study Research GroupDaytime sleepiness predicts mortality and cardiovascular disease in older adults.J Am Geriatr Soc. 2000; 48: 115-123Crossref PubMed Scopus (379) Google Scholar Therefore, it is quite conceivable that nonsleepy subjects with OSA enrolled in the RCTs2McEvoy 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: 919-931Crossref PubMed Scopus (1180) Google Scholar, 3Barbé F. Durán-Cantolla J. Sánchez 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: 2161-2168Crossref PubMed Scopus (589) Google Scholar, 4Peker Y. Glantz H. Eulenburg C. et al.Effect of positive airway pressure on cardiovascular outcomes in coronary artery disease patients with non-sleepy obstructive sleep apnea: the RICCADSA randomized controlled trial.Am J Respir Crit Care Med. 2016; 194: 613-620Crossref PubMed Scopus (367) Google Scholar might not have benefited from CPAP therapy. In the largest RCT,2McEvoy 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: 919-931Crossref PubMed Scopus (1180) Google Scholar the mean Epworth Sleepiness Scale score was about 7.5 units. However, sleepy subjects up to score of 15 units were enrolled. With this background, the question arises: what trial design has the best chance to achieve equipoise between effective CPAP and CV outcome? Does effective use of CPAP have any effect on incident CV disorders? The purpose of this commentary is to motivate further discussion, hoping eventually to lead to well thought out, definitive RCTs. We offer the following points:1.Patients included in an RCT should be representative of the population we are addressing.18Guerrera F. Renaud S. Tabbò Filosso P.L. How to design a randomized clinical trial: tips and tricks for conduct a successful study in thoracic disease domain.J Thorac Dis. 2017; 9: 2692-2696Crossref PubMed Scopus (17) Google Scholar Enrollment of patients from sleep clinics should be prioritized as they are more representative of the OSA patient profile, including EDS; thus, the findings of such trials would be easily extrapolated to patients with OSA seeking treatment. Importantly, sleepiness is usually reversed by CPAP therapy, hence, better long-term adherence is expected.2.Large observational studies, both population studies and those with established CV diseases, have shown that severe OSA (AHI ≥ 30 events/h) is consistently associated with excess CV mortality.19Young T. Finn L. Peppard P.E. et al.Sleep disordered breathing and mortality: eighteen-year follow-up of the Wisconsin Sleep Cohort.Sleep. 2008; 31: 1071-1078PubMed Google Scholar, 20Marshall N.S. Wong K.K. Liu P.Y. et al.Sleep apnea as an independent risk factor for all-cause mortality: the Busselton Health Study.Sleep. 2008; 31: 1079-1085PubMed Google Scholar, 21Punjabi N.M. Caffo B.S. Goodwin J.L. Sleep-disordered breathing and mortality: a prospective cohort study.PLoS Med. 2009; 6: e1000132Crossref PubMed Scopus (982) Google Scholar Thus, at least in a first step, an RCT should include only patients with severe OSA. The inclusion of patients with nonsevere OSA, in whom the deleterious CV effects of OSA are controversial, may lead to lack of effect of CPAP treatment, simply because nonsevere OSA has a low impact on “hard” CV outcomes. In the largest2McEvoy 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: 919-931Crossref PubMed Scopus (1180) Google Scholar of the aforementioned RCTs, the minimum AHI was 18 events/h (converted by authors from apnea link AHI to corresponding AHI based on current criteria).2McEvoy 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: 919-931Crossref PubMed Scopus (1180) Google Scholar, 22Gantner D. Ge J.Y. Li L.H. et al.Diagnostic accuracy of a questionnaire and simple home monitoring device in detecting obstructive sleep apnoea in a Chinese population at high cardiovascular risk.Respirology. 2010; 15: 952-960Crossref PubMed Scopus (54) Google Scholar, 23Ruehland W.R. Rochford P.D. O’Donoghue F.J. Pierce R.J. Singh P. Thornton A.T. The new AASM criteria for scoring hypopneas: impact on the apnea hypopnea index.Sleep. 2009; 32: 150-157Crossref PubMed Scopus (480) Google Scholar3.In addition to AHI ≥ 30 as the main metric, markers of hypoxia should be taken into account, because hypoxemia burden is believed to be the main underlying mediator of CV disorders and mortality.21Punjabi N.M. Caffo B.S. Goodwin J.L. Sleep-disordered breathing and mortality: a prospective cohort study.PLoS Med. 2009; 6: e1000132Crossref PubMed Scopus (982) Google Scholar, 24Xie J. Sert Kuniyoshi F.H. Covassin N. et al.Nocturnal hypoxemia due to obstructive sleep apnea is an independent predictor of poor prognosis after myocardial infarction.J Am Heart Assoc. 2016; 5: e003162Crossref PubMed Scopus (53) Google Scholar, 25Gami A.S. Olson E.J. Shen W.K. et al.Obstructive sleep apnea and the risk of sudden cardiac death.J Am Coll Cardiol. 2013; 62: 610-616Crossref PubMed Scopus (396) Google Scholar, 26Oldenburg O. Wellmann B. Buchholz A. et al.Nocturnal hypoxaemia is associated with increased mortality in stable heart failure patients.Eur Heart J. 2016; 37: 1695-1703Crossref PubMed Scopus (175) Google Scholar Yet, in the SAVE trial2McEvoy 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: 919-931Crossref PubMed Scopus (1180) Google Scholar patients with desaturation below 80% lasting 10 min were excluded, and subjects with ≥4% oxygen dip rate as low as 12 per hour were included, which could be one reason for lack of CPAP effect. Therefore, we suggest that severity of hypoxemia should not be an exclusion criterion, unless there is clinical evidence of hypoxemia-related events such as angina or significant arrhythmias (ventricular tachycardia) at night. Otherwise, we note that there is no evidence that treating any patients with OSA with any degree of hypoxemia leads to improved hard CV outcomes. In fact, ischemic preconditioning has been suggested as a reason for declining mortality in the senior population with OSA.27Lavie L. Lavie P. Ischemic preconditioning as a possible explanation for the age decline relative mortality in sleep apnea.Med Hypotheses. 2006; 66: 1069-1073Crossref PubMed Scopus (127) Google Scholar4.Regarding EDS, only very symptomatic patients should be excluded (see Randomization Concerns, below).5.In most of the few long-term RCTs the average age has been about 65 years. What is not reflected is the duration of OSA, which is impossible to determine. OSA is a long-standing disorder and the duration of the disease and potential for reversibility of its adverse CV effects are important concerns. Because a long-term trial for primary prevention of downstream CV disease involving younger, middle-aged participants is extremely costly, we suggest inclusion of such individuals in future trials. In RCTs, composite outcomes for fatal and nonfatal CV disease have been used because the incidence of the composite is higher than that of any of its components, allowing reduction in sample size and follow-up period, and increasing the statistical power. However, this approach has its concerns, especially when the clinical and prognostic weights of the components are not balanced, as happens with the composite combination of fatal stroke with TIA, or cerebrovascular and cardiovascular events.28Freemantle N. Calvert M. Wood J. Eastaugh J. Griffin C. Composite outcomes in randomized trials: greater precision but greater uncertainty?.JAMA. 2003; 289: 2554-2559Crossref PubMed Scopus (534) Google Scholar To counter this limitation, we advocate a single hard CV end point for which CPAP treatment could have the greatest probability of obtaining a beneficial effect. In this sense, there is considerable evidence showing that OSA is an important risk factor for incident stroke,29Kim Y. Koo Y.S. Lee H.Y. Lee S.Y. Can continuous positive airway pressure reduce the risk of stroke in obstructive sleep apnea patients? a systematic review and meta-analysis.PLoS One. 2016; 11: e0146317PubMed Google Scholar, 30Loke Y.K. Brown J.W. Kwok C.S. Niruban A. Myint P.H. Association of obstructive sleep apnea with risk of serious cardiovascular events: a systematic review and meta-analysis.Circ Cardiovasc Qual Outcomes. 2012; 5: 720-728Crossref PubMed Scopus (249) Google Scholar, 31Yaggi H.K. Concato J. Kernan W.N. et al.Obstructive sleep apnea as a risk factor for stroke and death.N Engl J Med. 2005; 353: 2034-2041Crossref PubMed Scopus (2372) Google Scholar and even the SAVE trial2McEvoy 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: 919-931Crossref PubMed Scopus (1180) Google Scholar reported a significant improvement in cerebrovascular outcomes with CPAP therapy (in a per-protocol analysis). Hence, this may be the most suitable hard CV outcome to address in a first phase. In contrast, the association between OSA and coronary heart disease (CHD) remains controversial and is not as strong as with stroke.29Kim Y. Koo Y.S. Lee H.Y. Lee S.Y. Can continuous positive airway pressure reduce the risk of stroke in obstructive sleep apnea patients? a systematic review and meta-analysis.PLoS One. 2016; 11: e0146317PubMed Google Scholar, 30Loke Y.K. Brown J.W. Kwok C.S. Niruban A. Myint P.H. Association of obstructive sleep apnea with risk of serious cardiovascular events: a systematic review and meta-analysis.Circ Cardiovasc Qual Outcomes. 2012; 5: 720-728Crossref PubMed Scopus (249) Google Scholar Several reasons may explain these findings, including the different pathophysiologic pathways of blood flow regulation (cerebral vascular bed is exposed to apnea-related fluctuations in systolic and diastolic blood pressure, whereas blood flow to the heart occurs only in diastole with overall much less coronary vascular stress) and the different impact of ischemic preconditioning phenomena on coronary vessels compared with the cerebral circulation.32Steiner S. Schueller P.O. Schulze V. Strauer B.E. Occurrence of coronary collateral vessels in patients with sleep apnea and total coronary occlusion.Chest. 2010; 137: 516-520Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar Therefore, CHD may not be the ideal outcome to begin with, and combining stroke with CHD as a composite end point could dilute the overall effect of CPAP therapy. However, for a composite outcome, regarding one organ, it would be preferable to combine outcomes with similar importance and weight (eg, combining fatal and nonfatal stroke, excluding TIA).18Guerrera F. Renaud S. Tabbò Filosso P.L. How to design a randomized clinical trial: tips and tricks for conduct a successful study in thoracic disease domain.J Thorac Dis. 2017; 9: 2692-2696Crossref PubMed Scopus (17) Google Scholar Although ideally, patients enrolled in RCTs should undergo polysomnography to diagnose OSA and exclude central sleep apnea (CSA), to lower the cost, we suggest the use of validated tools (eg, a type III device with two effort channels, oximetry, and pressure probe). The device used in the SAVE trial2McEvoy 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: 919-931Crossref PubMed Scopus (1180) Google Scholar consisted of a pressure probe and oximetry. A type III device allows the best minimal opportunity to exclude those with CSA, which could be prevalent in patients with stroke33Parra O. Arboix A. Bechich S. et al.Time course of sleep-related breathing disorders in first-ever stroke or transient ischemic attack.Am J Respir Crit Care Med. 2000; 161: 375-380Crossref PubMed Scopus (462) Google Scholar and left ventricular dysfunction,1Javaheri S. Barbe F. Campos-Rodriguez F. et al.Sleep apnea: types, mechanisms, and clinical cardiovascular consequences.J Am Coll Cardiol. 2017; 69: 841-858Crossref PubMed Scopus (598) Google Scholar, 34Lanfranchi P.A. Somers V.K. Braghiroli A. Corra U. Eleuteri E. Giannuzzi P. Central sleep apnea in left ventricular dysfunction: prevalence and implications for arrhythmic risk.Circulation. 2003; 107: 727-732Crossref PubMed Scopus (270) Google Scholar as such patients may not respond to CPAP therapy.35Arzt M. Floras J.S. Logan A.G. et al.Suppression of central sleep apnea by continuous positive airway pressure and transplant-free survival in heart failure: a post hoc analysis of the Canadian Continuous Positive Airway Pressure for Patients With Central Sleep Apnea and Heart Failure Trial (CANPAP).Circulation. 2007; 115: 3173-3180Crossref PubMed Scopus (561) Google Scholar, 36Javaheri S. CPAP should not be used for central sleep apnea in congestive heart failure patients.J Clin Sleep Med. 2006; 2: 399-402Crossref PubMed Scopus (50) Google Scholar Subjects enrolled in the SAVE trial2McEvoy 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: 919-931Crossref PubMed Scopus (1180) Google Scholar suffered from a large number of CV disorders. CPAP adherence is poor and gets worse with time, even in the best environment of research. Lack of adequate adherence could explain the poor outcomes of RCTs.2McEvoy 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: 919-931Crossref PubMed Scopus (1180) Google Scholar, 3Barbé F. Durán-Cantolla J. Sánchez 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: 2161-2168Crossref PubMed Scopus (589) Google Scholar, 4Peker Y. Glantz H. Eulenburg C. et al.Effect of positive airway pressure on cardiovascular outcomes in coronary artery disease patients with non-sleepy obstructive sleep apnea: the RICCADSA randomized controlled trial.Am J Respir Crit Care Med. 2016; 194: 613-620Crossref PubMed Scopus (367) Google Scholar The low adherence rates leave uncertainty concerning whether improved CPAP use would have been associated with better outcomes, as is evidenced from data in the literature. An early RCT37Pepperell J.C. Ramdassingh-Dow S. Crosthwaite N. et al.Ambulatory blood pressure after therapeutic and subtherapeutic nasal continuous positive airway pressure for obstructive sleep apnoea: a randomised parallel trial.Lancet. 2002; 359: 204-210Abstract Full Text Full Text PDF PubMed Scopus (899) Google Scholar showed that only CPAP-adherent patients benefit from the antihypertensive effect of CPAP and, in the HIPARCO (Hipertensión Arterial Resistente Control con CPAP) trial,38Martínez-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: 2407-2415Crossref PubMed Scopus (462) Google Scholar there was a close correlation between hours of CPAP use and drop in blood pressure. This is a critical issue because hypertension is the most important precursor of stroke and CHD, and small reductions in blood pressure, if sustained, with continued adherence to CPAP, will significantly decrease the downstream CV consequences of hypertension.39Williams B. Mancia G. Spiering W. et al.ESC Scientific Document Group2018 ESC/ESH guidelines for the management of arterial hypertension.Eur Heart J. 2018; 39: 3021-3104Crossref PubMed Scopus (4890) Google Scholar The pattern of CPAP use may have further contributed to the negative results of RCTs.2McEvoy 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: 919-931Crossref PubMed Scopus (1180) Google Scholar, 3Barbé F. Durán-Cantolla J. Sánchez 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: 2161-2168Crossref PubMed Scopus (589) Google Scholar, 4Peker Y. Glantz H. Eulenburg C. et al.Effect of positive airway pressure on cardiovascular outcomes in coronary artery disease patients with non-sleepy obstructive sleep apnea: the RICCADSA randomized controlled trial.Am J Respir Crit Care Med. 2016; 194: 613-620Crossref PubMed Scopus (367) Google Scholar Many patients with OSA sleep for a few hours with CPAP, only to wake up in the early morning hours, taking the mask off and sleeping a couple of more hours, which is when rapid eye movement (REM) sleep density is greatest. Studies40Mokhlesi B. Finn L.A. Hagen E.W. et al.Obstructive sleep apnea during REM sleep and hypertension: results of the Wisconsin Sleep Cohort.Am J Respir Crit Care Med. 2014; 190: 1158-1167Crossref PubMed Scopus (194) Google Scholar, 41Aurora R.N. Crainiceanu C. Gottlieb D.J. Kim J.S. Punjabi N.M. Obstructive sleep apnea during REM sleep and cardiovascular disease.Am J Respir Crit Care Med. 2018; 197: 653-660Crossref PubMed Scopus (87) Google Scholar suggest that OSA during REM sleep is associated with incident hypertension and cardiovascular outcomes. Therefore, in patients with REM-OSA, nonselective CPAP use may dwarf its CV benefit. In addition, obstructive apneas lengthen in late nonrapid eye movement (NREM) sleep,42Charbonneau M. Marin J.M. Kimoff R.J. Levy R.D. Cosio M.G. Changes in obstructive sleep apnea characteristics through the night.Chest. 1994; 106: 1695-1701Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar, 43Montserrat J.M. Kosmas E.N. Cosio M.G. Kimoff R.J. Mechanism of apnea lengthening across the night in obstructive sleep apnea.Am J Respir Crit Care Med. 1996; 154: 988-993Crossref PubMed Scopus (61) Google Scholar potentially further contributing to poor outcome in subjects with limited CPAP adherence. We, therefore propose a long run-in period with sham CPAP and exclusion of nonadherent subjects. This has been done in cardiology trials. For example, in the PARADIGM-HF (Prospective Comparison of ARNI [Angiotensin Receptor-Neprilysin Inhibitor] with ACEI [Angiotensin-Converting-Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial,44McMurray J.J. Packer M. Desai A.S. et al.Angiotensin-neprilysin inhibition versus enalapril in heart failure.N Engl J Med. 2014; 371: 993-1004Crossref PubMed Scopus (3899) Google Scholar there were two running-in periods (45 days). Overall, 2,079 eligible patients (20% of the total) were excluded for a variety of reasons, and finally 8,442 patients were randomized. Although it would be preferable to use CPAP rather than a sham device in a relatively long run-in period, participants who find CPAP helpful may decide not to enroll, resulting in bias. A combination of different methods for improving adherence over long follow-up periods should be incorporated. This would include educational, supportive, and behavioral interventions, the use of telemedicine, or even providing incentives and financial rewards to stimulate adherence.45Mitchell M.S. Goodman J.M. Alter D.A. et al.Financial incentives for exercise adherence in adults: systematic review and meta-analysis.Am J Prev Med. 2013; 45: 658-667Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar, 46Kushida C.A. Nichols D.A. Holmes T.H. 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: 1593-1602Crossref PubMed Scopus (272) Google Scholar We note that there is no accepted threshold in the number of daily hours of CPAP use clearly associated with an improvement in CV outcomes. It is possible that each individual CV outcome requires a different minimum nu
Referência(s)