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T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e

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CPAP versus Oxygen in Obstructive Sleep Apnea

Daniel J. Gottlieb, M.D., M.P.H., Naresh M. Punjabi, M.D., Ph.D., Reena Mehra, M.D., Sanjay R. Patel, M.D., Stuart F. Quan, M.D.,

Denise C. Babineau, Ph.D., Russell P. Tracy, Ph.D., Michael Rueschman, M.P.H., Roger S. Blumenthal, M.D., Eldrin F. Lewis, M.D., Deepak L. Bhatt, M.D., M.P.H.,

and Susan Redline, M.D., M.P.H.

From the Veterans Affairs Boston Healthcare System (D.J.G., D.L.B.), Brigham and Women’s Hospital (D.J.G., S.R.P., S.F.Q., M.R., E.F.L., D.L.B., S.R.), Harvard Medical School (D.J.G., S.R.P., S.F.Q., E.F.L., D.L.B., S.R.), Boston University School of Medicine (D.J.G.), and Beth Israel Deaconess Medical Center (S.R.P., S.R.) — all in Boston; Johns Hopkins University, Baltimore (N.M.P., R.S.B.); Cleveland Clinic (R.M.) and Case Western Reserve University (R.M., D.C.B.) — both in Cleveland; and the University of Vermont, Colchester (R.P.T.). Address reprint requests to Dr. Gottlieb at the Division of Sleep Medicine, Brigham and Women’s Hospital, 221 Longwood Ave., BLI 225E, Boston, MA 02115, or at [email protected].

A B S T R A C T

Background

Obstructive sleep apnea is associated with hypertension, inflammation, and in creased cardiovascular risk. Continuous positive airway pressure (CPAP) reduces blood pressure, but adherence is often suboptimal, and the benefit beyond manage ment of conventional risk factors is uncertain. Since intermittent hypoxemia may underlie cardiovascular sequelae of sleep apnea, we evaluated the effects of noctur nal supplemental oxygen and CPAP on markers of cardiovascular risk.

Methods

We conducted a randomized, controlled trial in which patients with cardiovascular disease or multiple cardiovascular risk factors were recruited from cardiology prac tices. Patients were screened for obstructive sleep apnea with the use of the Berlin questionnaire, and home sleep testing was used to establish the diagnosis. Participants with an apnea–hypopnea index of 15 to 50 events per hour were randomly assigned to receive education on sleep hygiene and healthy lifestyle alone (the control group) or, in addition to education, either CPAP or nocturnal supplemental oxygen. Cardio vascular risk was assessed at baseline and after 12 weeks of the study treatment. The primary outcome was 24hour mean arterial pressure.

Results

Of 318 patients who underwent randomization, 281 (88%) could be evaluated for ambulatory blood pressure at both baseline and followup. On average, the 24hour mean arterial pressure at 12 weeks was lower in the group receiving CPAP than in the control group (−2.4 mm Hg; 95% confidence interval [CI], −4.7 to −0.1; P = 0.04) or the group receiving supplemental oxygen (−2.8 mm Hg; 95% CI, −5.1 to −0.5; P = 0.02). There was no significant difference in the 24hour mean arterial pressure between the control group and the group receiving oxygen. A sensitivity analysis performed with the use of multiple imputation approaches to assess the effect of missing data did not change the results of the primary analysis.

Conclusions

In patients with cardiovascular disease or multiple cardiovascular risk factors, the treatment of obstructive sleep apnea with CPAP, but not nocturnal supplemental oxygen, resulted in a significant reduction in blood pressure. (Funded by the National Heart, Lung, and Blood Institute and others; HeartBEAT ClinicalTrials.gov number, NCT01086800.)

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Obstructive sleep apnea is a highly prevalent, chronic illness in adults, affecting an estimated 9% of middleaged wom en and 24% of middleaged men, with 4% and 9%, respectively, having moderatetosevere obstruc tive sleep apnea.1 Cohort studies have shown that obstructive sleep apnea is a risk factor for hy pertension, coronary heart disease, stroke, and death.2-9 The mechanisms underlying these as sociations are thought to include sympathetic activation, oxidative stress, and inflammation.10 Although reports from uncontrolled, clinicbased studies have indicated that cardiovascular risk is reduced among patients with obstructive sleep apnea who are treated with continuous positive airway pressure (CPAP) as compared with those who decline treatment,8,9,11,12 adequately powered randomized trials have not yet been conducted to evaluate the effect of CPAP on myocardial infarc tion, stroke, or death. One randomized trial de signed to evaluate cardiovascular risk reduction with CPAP was recently published, but it was lim ited by inadequate statistical power.13

A metaanalysis of small, unregistered, single center clinical trials showed a reduction of ap proximately 2 mm Hg in mean arterial pressure after CPAP treatment,14 and two multicenter clini cal trials involving patients with newly diagnosed obstructive sleep apnea showed modest improve ments in blood pressure with CPAP.15,16 In one of these studies, involving patients with untreated hypertension, the 24hour mean arterial pressure was reduced by 1.5 mm Hg (95% confidence in terval [CI], 0.4 to 2.7) over a 12week period of CPAP treatment.15 The other study, involving pa tients with hypertension who were not sleepy dur ing the day, showed a reduction in blood pressure (measured at an office visit while the patient was seated) of approximately 2 mm Hg over a 12month followup period16; fewer than half the patients were receiving antihypertensive therapy, and their mean blood pressure at baseline was approxi mately 141/85 mm Hg. Because the effect of CPAP on blood pressure in patients with obstructive sleep apnea and hypertension is much smaller than that of valsartan,17 it remains uncertain whether the specific treatment of obstructive sleep apnea provides an additional benefit beyond that achieved with adequate pharmacotherapy alone.

Moreover, the effectiveness of CPAP in reduc ing elevated blood pressure or preventing the de velopment of hypertension appears to be correlated

with hours of adherence,13,15,16,18,19 with effects in one study noted in only those participants who used CPAP for more than 5.6 hours per night.16 Since epidemiologic data have shown that most persons with obstructive sleep apnea do not re port excessive sleepiness,20 and since adherence to CPAP therapy is often poor in patients who are not sleepy during the day,21 less intrusive alternatives to CPAP are needed for the reduction of cardiovascular risk. Although obstructive sleep apnea probably increases the risk of cardiovas cular disease through a number of mechanisms, repetitive cycles of hypoxemia and reoxygenation are thought to play a central role by augmenting sympathetic nervous system activity, systemic in flammation, and oxidative stress.22-27 Consequent ly, it is believed that nocturnal supplemental oxy gen may serve as a potential alternative to CPAP in the reduction of cardiovascular risk. Although studies of supplemental oxygen treatment in pa tients with obstructive sleep apnea have shown that it can eliminate or markedly reduce noctur nal hypoxemia, in most of these studies, the apnea–hypopnea index (AHI) was not reduced when hypopnea was identified on the basis of a reduction in airflow, without regard to oxygen desaturation, and daytime functioning was not improved.28,29 In one small study in which CPAP and supplemental oxygen were compared with a sham CPAP control, only CPAP was found to sig nificantly reduce 24hour blood pressure; although supplemental oxygen appeared to be more effec tive than the control, the difference was not significant, and it was less effective than CPAP.30

In the present study, we sought to determine the effectiveness of both CPAP and supplemental oxygen as compared with usual care for reduc ing markers of cardiovascular risk in patients re cruited from cardiology practices, where the stan dard of care was likely to be high. The primary outcome measure was 24hour mean arterial blood pressure. Patients were also assessed for systemic inflammation, reactive hyperemia, fasting glyce mia, and dyslipidemia, and adherence to therapy was compared across the active treatment groups.

M e t h o d s

Study Design

The Heart Biomarker Evaluation in Apnea Treat ment (HeartBEAT) study was a foursite, random ized, parallelgroup clinical trial designed to as

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sess the effects of CPAP and supplemental oxygen therapy as compared with usual care in reducing cardiovascular risk among highrisk patients with obstructive sleep apnea. To assess the value these treatments may offer beyond that of con ventional riskfactor management, the study tar geted patients whose care was managed by cardi ologists, and education on habits promoting sleep hygiene (e.g., appropriate timing and duration of sleep) and a healthy lifestyle was provided to all participants. Cardiovascular risk factors were mea sured at baseline and after 12 weeks of treatment.

The research protocol was approved by the institutional review board of each participating institution. The study adhered to the protocol, which is available with the full text of this article at NEJM.org. All participants provided written informed consent. A data and safety monitoring board reviewed the protocol, monitored the prog ress of the study, and conducted a single interim analysis. The authors designed the study, oversaw data collection, performed the analyses, prepared the manuscript for publication, and made the decision to submit the manuscript for publica tion without input from or review by Philips Respironics, which donated equipment used in the study. All the authors vouch for the accuracy and completeness of the data.

Eligibility

Patients 45 to 75 years of age who were enrolled in cardiology practices at the four participating medical centers were screened for obstructive sleep apnea with the use of the Berlin questionnaire, which consists of three categories of questions related to the risk of sleep apnea: snoring and cessation of breathing, daytime sleepiness, and obesity or hypertension. Patients are considered to be at high risk if their scores are positive in two or more categories.31 Eligible patients had scores of 2 or 3 on the Berlin questionnaire and had established coronary heart disease or multi ple cardiovascular risk factors. At screening, par ticipants also completed the Epworth Sleepiness Scale, a selfreported measure of daytime sleepi ness with scores ranging from 0 to 24 and higher scores indicating more sleepiness. Detailed in clusion and exclusion criteria are provided in the Supplementary Appendix, available at NEJM.org.

Sleep tests of eligible participants were con ducted at their homes with the use of a portable

sleep monitor (Embletta Gold, Embla Systems), which assessed airflow by means of a nasal can nula pressure transducer and an oronasal ther mal sensor, thoracic and abdominal movement by means of inductance plethysmography, and oxygen saturation by means of pulse oximetry with a fingertip sensor. Body position was also moni tored, and threelead electrocardiography was used to monitor the heart. The studies were scored by a single certified scorer in accordance with guidelines from the American Academy of Sleep Medicine, which specify a reduction in airflow accompanied by a reduction in oxygen saturation of 3% or more as indicative of hypopnea.32 Participants were eligible for randomization if their AHI was 15 or more events (occurrences of apnea or hypopnea) per hour. Participants with severe obstructive sleep apnea, defined as an AHI above 50 or an oxygen saturation of less than 85% for more than 10% of the recording, were excluded from further participation, as were those with a central apnea index above 5.

Group Assignments and Interventions

After baseline evaluation, a stratified permuted block design was used to randomly assign par ticipants to one of three interventions: healthy lifestyle and sleep education (HLSE) alone (con trol), CPAP with HLSE, or supplemental oxygen with HLSE. All participants received standardized education in habits that promote improved sleep quality and reduce cardiovascular risk, including advice on diet and exercise. This information was based on guidelines from the American Heart Association. Participants in the CPAP group re ceived a CPAP device with automatic adjustment (REMstar Auto CPAP, Philips Respironics), set at a pressure range of 4 to 20 cm of water for 7 days and then reset to the best fixed pressure for each patient, defined as the 90th percentile of the pressure distribution generated through au tomatic adjustment during those 7 days (see the Supplementary Appendix). For the group receiv ing supplemental oxygen, a stationary oxygen con centrator (EverFlo, Philips Respironics) was used to provide nightly treatment with oxygen at a rate of 2 liters per minute through a nasal cannula.

Outcomes

Outcomes were measured at baseline and 12 weeks after randomization. The primary outcome was

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24hour mean arterial pressure (measured with the 90207 Ambulatory Blood Pressure Monitor, Spacelabs Healthcare). Mean pressure was calcu lated at each reading as one third of systolic pres sure plus two thirds of diastolic pressure. The 24hour mean pressure was calculated as a weighted average of the mean pressure during wakefulness and sleep, with weights determined by the percentage of reported time spent in each state, as recorded in a sleep diary. Nocturnal non dipping blood pressure was defined as a mean nocturnal blood pressure higher than 90% of the mean daytime value. Venipuncture was performed in the morning after a 12hour fast to measure serum levels of glucose, insulin, lowdensity lipo protein cholesterol, highdensity lipoprotein cho lesterol, total cholesterol, triglycerides, Nterminal pro–brain (Btype) natriuretic peptide (BNP), and highsensitivity Creactive protein. Endothelial function was assessed on the basis of the reactive hyperemia index, as measured with the use of the EndoPAT device (Itamar Medical) after an over night fast. Additional details are provided in the Supplementary Appendix.

Statistical Analysis

For outcomes measured on a continuous scale, the primary analysis at 12 weeks was based on an analysisofcovariance model with adjustment for the baseline value and stratification variables (study site and the presence or absence of coro nary artery disease). A Wald test was used to com pare the adjusted mean value for each outcome at 12 weeks between any two of the three groups, and the adjusted mean difference (and 95% con fidence interval) for each pairwise comparison was estimated. Residual analysis indicated that the normality assumption was violated for all bio chemical outcomes. Therefore, values were log transformed, and the adjusted geometric mean ratio between groups was estimated. Because of the persistence of outliers despite the use of log transformation, a robust regression model was used to analyze values for Creactive protein and Nterminal proBNP.33 A logisticregression model was used to model the logodds rate of nondip ping blood pressure at 12 weeks. A familywise type I error rate of 0.15 was chosen a priori to permit the detection of reasonable effect sizes with a sample that could be feasibly recruited within the time frame allowed by the grant, with

a Bonferronicorrected significance level of 0.05 for each pairwise comparison. Multiple imputa tion approaches were used to assess the sensitiv ity of the results from the primary analysis to missing data (see the Supplementary Appendix).

R e s u l t s

Study Population

Recruitment began in February 2010 and ended in September 2011, with the final followup visit completed in January 2012. Given a higherthan expected rate of study completion, 318 participants underwent randomization and 106 were assigned to each of the three study groups. A total of 301 participants (95%) completed the 12week study (Fig. 1). All participants received the assigned in tervention. Among the 301 participants who com pleted the study, 281 (93%) underwent 24hour bloodpressure monitoring at both baseline and 12 weeks. The 37 participants excluded from the primary analysis because of missing data for the monitoring of 24hour blood pressure were sig nificantly heavier than the other participants, and their reported usual sleep duration was signifi cantly shorter. The characteristics of these par ticipants were otherwise similar to those of the other participants, and their exclusion did not create any imbalances across the three groups.

The baseline characteristics of the partici pants who were evaluated at the 12week follow up visit were similar across groups, with sig nificant differences only in daytime sleepiness and in the proportion of participants who were receiving alphaadrenergic blockers (Table 1). Approximately half the participants had estab lished coronary heart disease, and 88% had hy pertension. Blood pressure was generally well controlled at baseline; the mean (±SD) number of antihypertensive medications that patients were receiving was 2.4±1.4, and the mean 24hour ar terial pressure was 124/71±15/8 mm Hg. The de gree of obstructive sleep apnea among the study participants was moderate to severe by design, although excessive daytime sleepiness was un common. The group receiving CPAP and the group receiving supplemental oxygen had similar re ductions in nocturnal hypoxemia, with each group having a reduction of at least 64% in the frequency of 3% desaturation events and a de cline of at least 2.6% in the percentage of sleep

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time during which oxygen saturation was below 90% (P<0.001 for the comparison of each of these groups with the control group); there was no significant difference in the rates of either event

between the CPAP group and the supplemental oxygen group. The mean duration of use of sup plemental oxygen was 4.8±2.4 hours per night, which was significantly greater than the duration

1034 Were eligible for home sleep testing

5747 Patients were assessed for eligibility

4713 Were excluded 3529 Did not meet inclusion criteria

1106 Had Berlin score of <2 or Epworth score of ≥16 2423 Were ineligible for reasons other than Berlin

or Epworth scores 1184 Were ineligible for reasons not recorded

846 Were enrolled for home sleep testing

188 Were excluded 178 Declined to participate 10 Had other reasons

318 Underwent randomization

528 Were excluded 51 Did not complete sleep testing

363 Had AHI of <15 events per hr 57 Had AHI of >50 events per hr 11 Had central apnea index of >5 5 Had SpO2 of <85% for >10% of recording

41 Had other reasons

106 Were assigned to NSO

5 Were excluded 2 Had adverse event 3 Withdrew owing to loss

of interest or dissatis- faction

106 Were assigned to CPAP

7 Were excluded 1 Was lost to follow-up 1 Withdrew owing to

coexisting illness 5 Withdrew owing to loss

of interest or dissatis- faction

106 Were assigned to HLSE

5 Were excluded 3 Were lost to follow-up 1 Was withdrawn for

administrative reasons 1 Withdrew

101 Were included in 12-wk follow-up 97 Were included in MAP analysis

99 Were included in 12-wk follow-up 90 Were included in MAP analysis

101 Were included in 12-wk follow-up 94 Were included in MAP analysis

Figure 1. Numbers of Patients Who Were Screened, Randomly Assigned to a Study Group, and Included in Follow-up Analyses.

AHI denotes apnea–hypopnea index, CPAP continuous positive airway pressure, HLSE healthy lifestyle and sleep education, MAP mean arterial pressure, and NSO nocturnal supplemental oxygen. The Berlin questionnaire consists of three categories of questions related to the risk of sleep apnea: snoring and cessation of breathing, daytime sleepiness, and obesity or hypertension. Patients are considered to be at high risk if their scores are positive in two or more categories. The Epworth Sleepiness Scale is a measure of daytime sleepiness, with higher scores indicating more sleepiness.

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of CPAP use, which was 3.5±2.7 hours per night (P = 0.001).

outcomes

The adjusted 24hour mean arterial pressure at 12 weeks was significantly lower in the group re ceiving CPAP than in either the control group or the

group receiving supplemental oxygen (Table 2). No significant difference in this measure was de tected between the group receiving supplemental oxygen and the control group. The results were almost identical when multiple imputation anal yses were used to account for missing data (CPAP vs. education alone, −2.4 mm Hg; P = 0.04; CPAP vs.

Table 1. Baseline Characteristics of the Study Population.*

Characteristic HLSE

(N = 97) CPAP

(N = 90) NSO

(N = 94)

Age — yr 63.1±7.7 63.5±7.0 62.9±7.3

Male sex — no. (%) 76 (78) 68 (76) 65 (69)

Race — no./total no. (%)†

White 79/95 (83) 75/89 (84) 69/93 (74)

Black 10/95 (11) 6/89 (7) 19/93 (20)

Other or unknown 6/95 (6) 8/89 (9) 5/93 (5)

Hispanic ethnic group — no./total no. (%)† 3/97 (3) 2/89 (2) 0/93 (0)

Body-mass index‡ 33.7±5.8 33.0±5.0 34.7±5.7

Coexisting condition — no./total no. (%)

Coronary artery disease 54/97 (56) 46/90 (51) 51/94 (54)

Diabetes mellitus 44/96 (46) 42/90 (47) 40/93 (43)

Hypertension 89/96 (93) 76/90 (84) 82/93 (88)

Medication use — no. (%)

ACE inhibitor or ARB 69 (71) 61 (68) 65 (69)

Beta-adrenergic blocker 68 (70) 53 (59) 69 (73)

Alpha-adrenergic blocker 2 (2) 0 (0) 6 (6)

Diuretic 36 (37) 33 (37) 39 (41)

Calcium-channel blocker 28 (29) 28 (31) 32 (34)

Lipid-lowering medication 85 (88) 82 (91) 83 (88)

Medication for diabetes 40 (41) 34 (38) 36 (38)

Smoking status — no. (%)

Current smoker 14 (14) 4 (4) 10 (11)

Former smoker 50 (52) 52 (58) 45 (48)

Apnea–hypopnea index — no. of events/hr 25.5±8.8 25.4±8.7 24.0±8.1

SpO2 <90% — % of recording time

Median 6.0 3.8 5.7

Interquartile range 2.4–11.7 1.6–8.7 2.1–13.2

Epworth Sleepiness Scale score§ 8.8±3.6 8.0±3.8 9.6±3.6

Reported usual sleep duration — hr 7.2±1.4 7.3±1.7 7.3±1.5

* Plus–minus values are means ±SD. There was a significant difference across groups for the use of alpha-adrenergic blockers and for the score on the Epworth Sleepiness Scale (P = 0.02); there were no significant differences for any of the other baseline characteristics (P>0.05). ACE denotes angiotensin-converting enzyme, ARB angiotensin-receptor blocker, CPAP continuous positive airway pressure, HLSE healthy lifestyle and sleep education, NSO nocturnal supple- mental oxygen, and SpO2 oxygen saturation level as measured by pulse oximetry.

† Race and ethnic group were self-reported. ‡ The body-mass index is the weight in kilograms divided by the square of the height in meters. § Scores on the Epworth Sleepiness Scale range from 0 to 24, with higher scores indicating more daytime sleepiness.

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supplemental oxygen, −2.8 mm Hg; P = 0.02; sup plemental oxygen vs. education alone, 0.3 mm Hg; P = 0.77). The magnitude of the effect of CPAP as compared with that of education alone or supple mental oxygen was somewhat larger for night time blood pressure than for daytime blood pres sure (Table 3). Although there was no significant treatment effect on the odds of nondipping noc turnal blood pressure, the odds in the group re ceiving CPAP were 40% lower than the odds in the control group (odds ratio, 0.60; 95% confi dence interval [CI], 0.32 to 1.11; P = 0.10), and the odds in the group receiving supplemental oxygen were 15% lower than the odds in the control group (odds ratio, 0.85; 95% CI, 0.46 to 1.56; P = 0.60). A secondary analysis with further ad justment for age, sex, race, baseline bodymass index, AHI, and use or nonuse of each class of antihypertensive medication had no appreciable influence on the effect estimates.

Analysis of the reactive hyperemia index at 12 weeks revealed no evidence of significant differ ences among the three groups. CPAP was associ ated with a significantly lower adjusted level of Creactive protein at 12 weeks than was educa tion alone (geometric mean ratio, 0.80; 95% CI, 0.65 to 0.97; P = 0.03); no significant difference in levels of other laboratory values was detected (Tables S1 and S2 in the Supplementary Appendix).

There was no significant association between hours of CPAP use and 24hour mean arterial pressure, although nocturnal systolic blood pres sure fell significantly for each additional hour of CPAP use per night (−0.93 mm Hg per hour;

95% CI, −1.77 to −0.10; P = 0.03). In addition, the odds of nondipping nocturnal blood pressure fell sharply with each additional hour of CPAP use (odds ratio, 0.76 per hour; 95% CI, 0.63 to 0.92; P = 0.006). No significant differences among groups were observed in the rate of nonserious or serious adverse events (see the Supplementary Appendix).

D i s c u s s i o n

The present study shows that among patients with previously undiagnosed moderatetosevere obstructive sleep apnea, treatment with CPAP re sulted in reduced 24hour mean arterial pres sure, even in a clinical setting in which cardio vascular risk factors, including blood pressure, were well managed and despite the exclusion of patients with the most severe obstructive sleep apnea, who might be expected to derive the great est benefit from treatment. Although the average decrease in blood pressure resulting from CPAP was modest as compared with the effect of anti hypertensive medications, the treatment effect was observed in patients who were already re ceiving these medications. The reduction in blood pressure was similar to that in prior studies of the treatment of obstructive sleep apnea14-17 and was of a magnitude associated with a meaning ful reduction in cardiovascular risk. A metaanal ysis of 61 observational studies that evaluated the relation of blood pressure to mortality from vas cular disease showed that a reduction of 2 mm Hg in systolic blood pressure would reduce mortality

Table 2. Effect of Treatment on 24-Hour Blood Pressure.*

Variable CPAP

(N = 90) NSO

(N = 94) HLSE

(N = 97) CPAP vs. HLSE NSO vs. HLSE CPAP vs. NSO

24-Hr mean arterial blood pressure

Baseline 89.5±8.6 88.6±10.0 87.7±9.3

12 Wk 87.8±8.1 90.2±11.1 89.0±11.2 −2.4 (P = 0.04) 0.4 (P = 0.71) −2.8 (P = 0.02)

24-Hr mean systolic blood pressure

Baseline 124.7±13.5 125.3±16.9 123.6±14.3

12 Wk 123.4±12.8 126.9±16.5 124.7±16.4 −1.9 (P = 0.25) 1.2 (P = 0.45) −3.1 (P = 0.06)

24-Hr mean diastolic blood pressure

Baseline 72.0±7.7 70.8±8.3 69.6±8.6

12 Wk 69.8±7.5 71.7±9.8 70.9±10.1 −2.8 (P = 0.005) −0.1 (P = 0.95) −2.8 (P = 0.006)

* Plus–minus values are means ±SD. The between-group differences are the mean differences at 12 weeks, adjusted for study site, presence or absence of coronary artery disease, and blood pressure as measured at baseline. CPAP denotes continuous positive airway pressure, NSO nocturnal supplemental oxygen, and HLSE healthy lifestyle and sleep education.

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from stroke by 10% and mortality from ischemic heart disease or other vascular causes by 7%, with reductions in diastolic blood pressure having ef fects that were approximately twice as large.34 A metaanalysis of 147 randomized trials showed effects of similar magnitude for stroke and events related to coronary heart disease, even in patients with blood pressure as low at 110/70 mm Hg before treatment.35 The effect of CPAP appears to be greatest at night, perhaps reflect ing the prevention of postapneic increases in blood pressure and indicating that CPAP may thereby lower the cardiovascular risk associated with the absence of a normal nocturnal reduc tion in blood pressure.36

Since patients were recruited from general cardiology practices rather than from referral cen ters for sleep disorders, most participants had

only mild symptoms of obstructive sleep apnea, and adherence to treatment with CPAP was some what lower (i.e. fewer hours of nightly use) than that reported in several European studies.13,15-18 The beneficial effect of CPAP, despite modest average adherence levels, may be relevant to pub lic policy, given the common use of adherence data to restrict reimbursement for CPAP to patients whose adherence exceeds a specified threshold. However, the study was not powered to deter mine a critical adherence threshold for the ben eficial effect of CPAP, and further clarification of the dose–response relationship is needed.

Although observational studies have generally shown that obstructive sleep apnea is associated with inflammation and with impaired fasting glycemia or overt diabetes mellitus, intervention studies have yielded inconsistent results.37,38 In

Table 3. Effect of Treatment on Nighttime and Daytime Blood Pressure.*

Variable CPAP

(N = 93) NSO

(N = 95) HLSE

(N = 97)† CPAP vs. HLSE NSO vs. HLSE CPAP vs. NSO

Nighttime mean arterial blood pressure

Baseline 83.0±9.9 82.1±10.4 80.7±9.8

12 Wk 80.9±9.3 83.9±12.1 82.9±12.9 −3.5 (P = 0.005) −0.0 (P = 0.97) −3.5 (P = 0.005)

Nighttime mean systolic blood pressure

Baseline 116.6±15.7 117.0±17.8 115.5±15.7

12 Wk 114.7±14.9 119.3±17.8 117.4±19.3 −3.3 (P = 0.11) 0.9 (P = 0.60) −4.2 (P = 0.02)

Nighttime mean diastolic blood pressure

Baseline 66.2±8.4 64.7±8.2 63.4±8.5

12 Wk 64.1±8.1 66.1±10.5 65.6±10.9 −3.7 (P = 0.001) −0.5 (P = 0.61) −3.2 (P = 0.003)

Daytime mean arterial blood pressure

Baseline 92.4±8.9 91.8±10.6 90.7±9.9

12 Wk 90.5±8.5 92.8±11.3 91.6±11.4 −2.1 (P = 0.09) 0.5 (P = 0.66) −2.6 (P = 0.04)

Daytime mean systolic blood pressure

Baseline 128.0±13.6 128.7±17.1 127.2±14.6

12 Wk 126.8±12.9 130.2±17.0 128.0±16.0 −1.7 (P = 0.33) 1.2 (P = 0.50) −2.9 (P = 0.10)

Daytime mean diastolic blood pressure

Baseline 74.6±8.2 72.4±9.1 72.4±9.2

12 Wk 72.4±7.9 74.2±9.9 73.4±10.6 −2.5 (P = 0.02) 0.1 (P = 0.91) −2.6 (P = 0.02)

† For the measurement of daytime blood pressure, the number of participants in the group receiving HLSE was 99.

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the present study, the CPAP group had a 20% reduction in the mean level of Creactive protein at 12 weeks, as compared with the control group, although this finding should be interpreted with caution, since no significant treatment effects were observed for other biochemical measures. It is possible that the recruitment of patients from cardiology practices, which provided effective risk factor management at baseline, limited our abil ity to detect further improvement in biochemical measures.

In contrast to the beneficial effects of CPAP on blood pressure, the use of supplemental oxy gen was not associated with a reduction in blood pressure, even though adherence was greater among patients receiving supplemental oxygen. This finding was unexpected, since intermittent hypoxemia induces sustained elevations in blood pressure in both rodents23 and humans.39 More over, in dog models of obstructive sleep apnea, obstructive apneas result in sustained hyperten sion, whereas arousals of a similar frequency caused by sound do not,40 and supplemental oxy gen markedly attenuates the immediate hyper tensive response to obstructive apneas.24 Since CPAP and supplemental oxygen had similar effects on nocturnal hypoxemia, the lack of a beneficial effect of supplemental oxygen could indicate that other factors (e.g., arousal, hypercapnia, and large

swings in intrathoracic pressure) play a role in hypertension resulting from obstructive sleep ap nea; however, in the absence of more detailed physiological measures, our ability to draw mech anistic inferences from these data is limited.

In conclusion, the treatment of obstructive sleep apnea with CPAP, but not with nocturnal supplemental oxygen, results in a significant re duction in blood pressure, even in patients with wellcontrolled hypertension at baseline. Although there may be other clinical reasons that a treat ing physician should consider using supplemen tal oxygen in specific patients, this study offers no support for the common but largely untested clinical practice of providing supplemental oxy gen as salvage therapy in patients with obstruc tive sleep apnea for whom CPAP is problematic.

Supported by grants from the National Heart, Lung, and Blood Institute (RC2 HL101417, 1R01HL109493, and R21HL108226) and by a grant from the National Center for Research Resources (UL1 RR024989).

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

We thank the members of the data safety and monitoring board (Wayne Cascio, M.D., chair; Vernon M. Chinchilli, Ph.D.; William Cotts, M.D.; Patrick Strollo, M.D.; and Terri Weaver, R.N., Ph.D.) for providing expert and timely guidance and over sight, and the study staff (Joan Aylor, Amanda Barbeau, Denise P. Clarke, Daniel Cooper, Kelly Devine, Anna Maria Kibler, Melissa Minotti, Rawan Nawabit, Gaynor A. Stephens, Ashley Wagner, Cynthia Williams, and Christina L. Zenobi) for their invaluable assistance.

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