Correspondence
Sleep Apnea and Heart Disease
N Engl J Med 2006; 354:1086-1089March 9, 2006
- Article
To the Editor:
Bradley and colleagues (Nov. 10 issue)1 report that treatment with continuous positive airway pressure (CPAP) in patients with heart failure and central sleep apnea did not affect morbidity and mortality, although several functional measures significantly improved. During the period of their study (the Canadian Continuous Positive Airway Pressure for Patients with Central Sleep Apnea and Heart Failure [CANPAP] trial), the primary event rate (death and cardiac transplantation) fell significantly. As discussed, this improvement was paralleled by a changing pattern of drug therapy for heart failure. Unfortunately, the use of implantable cardioverter–defibrillators and pacemakers for cardiac-resynchronization therapy was not discussed. Both implantable cardioverter–defibrillators and pacemakers may significantly reduce overall mortality in selected patients with heart failure.2,3 Furthermore, it has recently been demonstrated that cardiac-resynchronization therapy alone not only can reduce the apnea–hypopnea index4 but also can improve sleep quality, the quality of life, and symptomatic depression,5 while avoiding any potential detrimental effects of CPAP on cardiac function. Therefore, in order to reduce morbidity and mortality, it might be more promising to target sudden death and left ventricular failure more directly before initiating CPAP therapy in these patients.
5 ReferencesAnil-Martin Sinha, M.D., D.Phil.
Klinikum Coburg, 96450 Coburg, Germany
amsinha@gmx.de Erik C. Skobel, M.D.
Center for Cardiac and Pulmonary Rehabilitation, 52066 Aachen, GermanyOle-Alexander Breithardt, M.D.
Universitätsklinikum Mannheim, 68167 Mannheim, Germany1
Bradley TD ,Logan AG ,Kimoff RJ , et al. Continuous positive airway pressure for central sleep apnea and heart failure. N Engl J Med 2005;353:2025-2033
Full Text | Web of Science | Medline2
Cleland JG ,Daubert JC ,Erdmann E , et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005;352:1539-1549
Full Text | Web of Science | Medline3
Moss AJ ,Zareba W ,Hall WJ , et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med 2002;346:877-883
Full Text | Web of Science | Medline4
Sinha AM ,Skobel EC ,Breithardt OA , et al. Cardiac resynchronization therapy improves central sleep apnea and Cheyne-Stokes respiration in patients with chronic heart failure. J Am Coll Cardiol 2004;44:68-71
CrossRef | Web of Science | Medline5
Skobel EC ,Sinha AM ,Norra C , et al. Effect of cardiac resynchronization therapy on sleep quality, quality of life, and symptomatic depression in patients with chronic heart failure and Cheyne-Stokes respiration. Sleep Breath 2005;9:159-166
CrossRef | Medline
To the Editor:
Bradley and colleagues report that the use of CPAP in patients who have central sleep apnea and heart failure does not have an effect on survival rate. However, numerous studies1-3 have shown that the baseline level of norepinephrine is a significant independent predictor of death in patients with congestive heart failure. It is notable that the CPAP group in this trial had a higher baseline norepinephrine level than did the control group (mean [±SD] level, 3.0±2.0 vs. 2.3±1.1 nmol per liter). The authors do not indicate whether this difference was statistically significant. Furthermore, norepinephrine levels were available for less than one third of patients in both groups. The higher baseline norepinephrine level in the CPAP group may have confounded the effect of therapy on survival.
3 ReferencesHaoyi Zheng, M.D.
Huichun Zhan, M.D.
Long Island Jewish Medical Center, New Hyde Park, NY 11040
hyzheng@yahoo.com 1
Bristow MR ,Krause-Steinrauf H ,Nuzzo R , et al. Effect of baseline or changes in adrenergic activity on clinical outcomes in the beta-Blocker Evaluation of Survival Trial. Circulation 2004;110:1437-1442
CrossRef | Web of Science | Medline2
Cohn JN ,Levine TB ,Olivari MT , et al. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med 1984;311:819-823
Full Text | Web of Science | Medline3
Kaye DM ,Lefkovits J ,Jennings GL ,Bergin P ,Broughton A ,Esler MD . Adverse consequences of high sympathetic nervous activity in the failing human heart. J Am Coll Cardiol 1995;26:1257-1263
CrossRef | Web of Science | Medline
To the Editor:
Central sleep apnea is a consequence of heart failure in some but not all patients.1 A key question is whether eliminating this sleep disorder is beneficial. In the study by Bradley et al., CPAP had no effect on survival or freedom from transplantation after three months, as compared with untreated controls. CPAP therapy, which was used by 85 percent of treated subjects, reduced the number of episodes of central apnea by 50 percent and was used for approximately four hours per night. Thus, CPAP reduced the sleep-breathing disorder by roughly 25 percent — a substantial undertreatment effect and a potential confounder of the study conclusions.
The initial approach to central sleep apnea in heart failure should be the optimal treatment of heart failure, including pharmacologic and device-based therapies.2,3 There are a variety of approaches to suppressing residual central sleep apnea: the administration of oxygen, fixed-pressure CPAP, and such newer approaches as nasal ventilation4 and adaptive servo-ventilation5 (“breathing resynchronization”), which may eliminate central sleep apnea in heart failure more effectively than does fixed-pressure CPAP.
Ian Wilcox, Ph.D., F.R.A.C.P.
University of Sydney, Sydney, NSW 2006, Australia
iw@mail.med. usyd. edu. au Virginia Booth, R.N.
JoDee Lattimore, Ph.D., F.R.A.C.P.
Royal Prince Alfred Hospital, Sydney, NSW 2050, AustraliaDr. Wilcox reports serving as a consultant to Resmed and holding a minor equity interest in the company.
5 References1
Wilcox I ,McNamara SG ,Wessendorf T ,Willson GN ,Piper AJ ,Sullivan CE . Prognosis and sleep disordered breathing in heart failure. Thorax 1998;53:Suppl 3:S33-S36
CrossRef | Web of Science | Medline2
Garrigue S ,Bordier P ,Jais P , et al. Benefit of atrial pacing in sleep apnea syndrome. N Engl J Med 2002;346:404-412
Full Text | Web of Science | Medline3
Gabor JY ,Newman DA ,Barnard-Roberts V , et al. Improvement in Cheyne-Stokes respiration following cardiac resynchronisation therapy. Eur Respir J 2005;26:95-100
CrossRef | Web of Science | Medline4
Willson GN ,Wilcox I ,Piper AJ , et al. Noninvasive pressure preset ventilation for the treatment of Cheyne-Stokes respiration during sleep. Eur Respir J 2001;17:1250-1257
CrossRef | Web of Science | Medline5
Teschler H ,Dohring J ,Wang YM ,Berthon-Jones M . Adaptive pressure support servo-ventilation: a novel treatment for Cheyne-Stokes respiration in heart failure. Am J Respir Crit Care Med 2001;164:614-619
Web of Science | Medline
To the Editor:
The obstructive sleep apnea syndrome is a clinical entity that comprises an elevated apnea–hypopnea index together with increased daytime sleepiness.1 Yaggi et al. (Nov. 10 issue)2 have analyzed a cohort of patients with an elevated apnea–hypopnea index and have drawn conclusions from these observations regarding the obstructive sleep apnea syndrome. The mean score on the Epworth Sleepiness Scale for subjects in the study who were diagnosed with sleep apnea was 11, as compared with 10 for controls. Therefore, it is unlikely that the entire study population had daytime sleepiness. In addition, the mean arousal index for the controls was unusually high at 26, which raises questions about coexisting sleep conditions and the quality of the polysomnography.3 The cardiovascular consequences for patients with a mildly elevated apnea–hypopnea index without daytime somnolence are debatable. The study by Yaggi et al. suggests further questions. First, should everybody be screened for an elevated apnea–hypopnea index? Second, should patients with a mild elevation of the apnea–hypopnea index without daytime somnolence be treated?
3 ReferencesPrashant N. Chhajed, M.D.
Michael Tamm, M.D.
Werner Strobel, M.D.
University Hospital Basel, CH-4031 Basel, Switzerland
pchhajed@uhbs.ch 1
Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research -- the report of an American Academy of Sleep Medicine Task Force. Sleep 1999;22:667-689
Web of Science | Medline2
Yaggi HK ,Concato J ,Kernan WN ,Lichtman JH ,Brass LM ,Mohsenin V . Obstructive sleep apnea as a risk factor for stroke and death. N Engl J Med 2005;353:2034-2041
Full Text | Web of Science | Medline3
Martin SE ,Engleman HM ,Kingshott RN ,Douglas NJ . Microarousals in patients with sleep apnoea/hypopnoea syndrome. J Sleep Res 1997;276:276-280
CrossRef | Web of Science
To the Editor:
Yaggi et al. report that the obstructive sleep apnea syndrome significantly increases the risk of stroke or death from any cause. This increase was independent of several other risk factors. However, data on atrial size and ventricular function were not reported. This information is crucial, because atrial dilatation and ventricular dysfunction are known to be independently associated with an increased risk of stroke.1-3
3 ReferencesHans-Ruprecht Neuberger, M.D.
Michael Böhm, M.D.
Christian Mewis, M.D.
Universitätsklinik für Innere Medizin III, D-66421 Homburg/Saar, Germany
h.neuberger@tiscali. de 1
Benjamin EJ ,D'Agostino RB ,Belanger AJ ,Wolf PA ,Levy D . Left atrial size and the risk of stroke and death. Circulation 1995;92:835-841
Web of Science | Medline2
Di Tullio MR ,Sacco RL ,Sciacca RR ,Homma S . Left atrial size and the risk of ischemic stroke in an ethnically mixed population. Stroke 1999;30:2019-2024
CrossRef | Web of Science | Medline3
Loh E ,Sutton MS ,Wun CC , et al. Ventricular dysfunction and the risk of stroke after myocardial infarction. N Engl J Med 1997;336:251-257
Full Text | Web of Science | Medline
Author/Editor Response
At the inception of the CANPAP trial, the only intervention for central sleep apnea in heart failure that had shown a benefit in short-term randomized trials was CPAP.1 Newer interventions to suppress central sleep apnea, as proposed by Sinha et al. and Wilcox et al., are of interest, but none of these treatments have been tested in randomized trials with hard cardiovascular end points; we encourage these correspondents to do so. Indeed, no reports of randomized trials demonstrate that biventricular pacing suppresses central sleep apnea nor has atrial overdrive pacing been shown to benefit patients similar to those enrolled in CANPAP.2 The study of biventricular pacing by Skobel et al. was not randomized and included only 18 patients with very mild central sleep apnea who were studied for only three to four months, during which 15 percent dropped out. Whether the 67 percent reduction in the apnea–hypopnea index that accompanied biventricular pacing can be achieved in patients with more severe central sleep apnea — and whether such a reduction can be sustained for a prolonged period — are questions that have not been tested. Garrigue et al. did not study the effect of atrial overdrive pacing on central sleep apnea in patients with heart failure, and their findings have not been replicated in subsequent trials.2,3
With regard to the comments by Zheng and Zhan: baseline plasma norepinephrine concentrations, in addition to all other baseline variables, were not significantly different in the two groups, as indicated in the first footnote to Table 1 of our article.
We agree with Wilcox et al. that the initial approach to central sleep apnea in heart failure should be optimal pharmacologic therapy. Indeed, a careful reading of our paper would inform these correspondents that such optimization was an entry criterion for CANPAP and that it evolved as evidence from randomized trials became available during the trial. We believe this was one reason for the reduction in the cardiovascular event rate that led to the early termination of CANPAP. As suggested by Sinha et al., devices might also have contributed to this reduced rate. Six trial subjects received biventricular pacemakers (2.3 percent), and 31 subjects had defibrillators with or without resynchronization therapy (12 percent). Implantation rates over the course of the trial were similar in the two groups.
We also agree with Wilcox et al. that further testing would show whether greater suppression of central sleep apnea might improve survival. Unfortunately, their estimate of suppression of central sleep apnea by CPAP is faulty. To arrive at their figure of a reduction of 25 percent in central sleep apnea, they must have assumed a total sleep time of eight hours. However, the mean sleep time in the CANPAP study was only five hours (as stated in Table 1 of our article). Since patients used CPAP for four hours per night (80 percent of the total sleep time) and there was a 50 percent reduction in the frequency of episodes of apnea and hypopnea, the reduction in the burden of central sleep apnea was 40 percent, not 25 percent. Because the mean follow-up in CANPAP was two years, their suggestion that CPAP had no effect on survival after three months is misleading. The 85 percent compliance with CPAP achieved in CANPAP indicates a high level of patient acceptability. Wilcox et al. provide no evidence that they have been able to achieve similar rates of 85 percent compliance and 50 percent reduction in the apnea–hypopnea index over two years with the use of the interventions they propose.
3 ReferencesT. Douglas Bradley, M.D.
Toronto General Hospital, Toronto, ON M5G 2C4, Canada
douglas.bradley@utoronto. ca John S. Floras, M.D., D.Phil.
Alexander G. Logan, M.D.
University of Toronto, Toronto, ON M5G 2C4, Canada1
Naughton MT ,Liu PP ,Bernard DC ,Goldstein RS ,Bradley TD . Treatment of congestive heart failure and Cheyne-Stokes respiration during sleep by continuous positive airway pressure. Am J Respir Crit Care Med 1995;151:92-97
Web of Science | Medline2
Floras JS ,Bradley TD . Atrial overdrive pacing for sleep apnea: a door now closed? Am J Respir Crit Care Med 2005;172:1-3
CrossRef | Web of Science | Medline3
Luthje L ,Unterberg-Buchwald C ,Dajani D ,Vollmann D ,Hasenfuss D ,Andreas S . Atrial overdrive pacing in patients with sleep apnea with implanted pacemaker. Am J Respir Crit Care Med 2005;172:118-122
CrossRef | Web of Science | Medline
Author/Editor Response
Dr. Chhajed and colleagues ask whether everyone should be screened for an elevated apnea–hypopnea index and whether patients with a mild elevation of the index without daytime somnolence should be treated. On the basis of current evidence, including our recent study, screening for apnea and hypopnea in otherwise healthy adults is not justified. Our finding that sleep apnea increased the risk of stroke or death was obtained among patients who were referred to a sleep center for suspected sleep-disordered breathing. Virtually all the patients in our study reported either daytime somnolence or snoring or pauses in breathing noted during sleep. Therefore, we would be reluctant to extrapolate the results to a healthier population. Given the high prevalence of sleep apnea, however, health care providers should have a low threshold for the further evaluation of patients with symptoms suggestive of this disorder.
Regarding the second question, there is little agreement regarding the severity of sleep apnea that requires treatment, but even a mild elevation in the frequency of apnea and hypopnea is associated with stroke, myocardial infarction, and congestive heart failure.1 In addition, the current concept of disease severity, derived on the basis of cutoffs of the apnea–hypopnea index and the presence of sleepiness, is somewhat arbitrary regarding the risk of cardiovascular disease and stroke. There is a need to better understand and measure such a risk by considering the severity of oxygen desaturation and other factors as part of an overall cardiovascular-risk profile. Furthermore, both screening for sleep apnea and the treatment of mild sleep-disordered breathing require studies demonstrating the efficacy of treatment in reducing stroke.
We agree with Dr. Neuberger and colleagues that atrial dilatation and ventricular dysfunction are risk factors for stroke. However, the inclusion of these variables (particularly ventricular dysfunction) in an analysis of this kind could be an overadjustment by controlling for factors that might explain how sleep apnea causes stroke. For example, obstructive sleep apnea is associated with heart failure independent of other known factors,1 and heart failure is linked independently to stroke. A long-term study examining the natural history of untreated sleep apnea would be needed to determine the complete sequence of events that link sleep apnea with stroke.
1 ReferencesH. Klar Yaggi, M.D., M.P.H.
John Concato, M.D., M.P.H.
Vahid Mohsenin, M.D.
Yale University School of Medicine, New Haven, CT 065201
Shahar E ,Whitney CW ,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
Web of Science | Medline
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