Francisco Campos-Rodriguez, MD; Jose Perez-Ronchel, MD; Antonio Grilo-Reina, MD; Jorge Lima-Alvarez, MD; Maria A. Benitez, MD and Carmen Almeida-Gonzalez, MD

CHEST.  2007;132(6):1847-1852.  ©2007 American College of Chest Physicians

Abstract and Introduction

Abstract

Objective: To analyze the long-term effect of continuous positive airway pressure (CPAP) on ambulatory BP in patients with obstructive sleep apnea (OSA) and hypertension, and to identify subgroups of patients for whom CPAP could be more effective.
Methods: We conducted a prospective, long-term follow-up trial (24 months) in 55 patients with OSA and hypertension (mean CPAP use, 5.3 ± 1.9 h/d [± SD]). Twenty-four-hour ambulatory BP monitoring (ABPM) was measured at baseline and after intervention with CPAP on an intention-to-treat basis. In addition, the correlation between the changes in 24-h mean arterial pressure (24hMAP) and CPAP compliance, OSA severity, and baseline ABPM was assessed.
Results: At the end of follow-up, a significant decrease was shown only in diastolic BP (- 2.2 mm Hg; 95% confidence interval [CI], - 4.2 to - 0.1; p = 0.03) but not in 24hMAP or other ABPM parameters. However, a correlation between changes in 24hMAP and baseline systolic BP (r = - 0.43, p = 0.001), diastolic BP (r = - 0.38, p = 0.004), and hours of use of CPAP (r = - 0.30, p = 0.02) was observed. A significant decrease in the 24hMAP was achieved in a subgroup of patients with incompletely controlled hypertension at entry (- 4.4 mm Hg; 95% CI, - 7.9 to - 0.9 mm Hg; p = 0.01), as well as in those with CPAP compliance > 5.3 h/d (- 5.3 mm Hg; 95% CI, - 9.5 to - 1.2 mm Hg; p = 0.01). Linear regression analysis showed that baseline systolic BP and hours of CPAP were independent predictors of reductions in BP with CPAP.
Conclusion: Long-term CPAP reduced BP modestly in the whole sample. However, patients with higher BP at entry and good CPAP compliance achieved significant reductions in BP.

Introduction

Obstructive sleep apnea (OSA) syndrome, a disorder affecting 2 to 4% of the adult population,^[1] is an independent risk factor for arterial hypertension^[2,3] and has been identified as the first identifiable cause of hypertension.^[4] Continuous positive airway pressure (CPAP) is the treatment of choice for symptomatic OSA, and well-designed trials^[5,6] have shown that CPAP improves daytime function as well as quality of life in these patients. Furthermore, it has been reported that CPAP reduces sympathetic activity, production of free oxygen radicals, and reverses the endothelial dysfunction caused by OSA.^[7-9] Hence, CPAP treatment should have a beneficial effect on BP in patients with OSA and hypertension. However, data on the effect of CPAP on BP are not conclusive. Randomized placebo-controlled trials^[10-16] have shown conflicting resultswith either a clear improvement or only minor but insignificant reductions in BP. However, even if CPAP were useful in reducing BP in the short term, it would be necessary to demonstrate if it persists in the long term. Results of studies^[7,17-24] analyzing the long-term effect of CPAP on BP are controversial due to heterogeneous study designs that included normotensive patients, short follow-ups, and small sample sizes. Therefore, the aims of this study were to analyze the long-term effect of CPAP on ambulatory BP in a population of patients with OSA and hypertension receiving antihypertensive treatment and to identify subgroups of patients for whom CPAP treatment might be more effective.

Materials and Methods

Design and Patients

A prospective, long-term follow-up trial of consecutive patients referred to the Sleep Disorders Unit of the Valme University Hospital (Seville, Spain) between January and September 2003 with a suspected diagnosis of OSA was conducted. Patients were considered for inclusion if they were between 30 and 70 years of age with an apnea-hypopnea index (AHI) ≥ 10/h in conventional polysomnography, and a previous diagnosis of hypertension and receiving treatment with at least one drug for at least 3 months previous to the inclusion in the study. Patients were excluded if they had > 30% of central apnea, malignancy, respiratory or heart failure, secondary hypertension, or have previously participated in clinical trials. The local ethics committee of the hospital approved the trial protocol, and patients gave written informed consent.

Procedures

Hypertension was defined as systolic BP > 140 mm Hg or diastolic BP > 90 mm Hg in three independent measurements using a conventional sphygmomanometer.^[4] OSA diagnosis was based on standard polysomnography (Ultrasom; Nicolette Biomedical; Madison, WI) during a full night in the sleep laboratory. Polysomnography was performed according to standard criteria as detailed previously.^[14]

Ambulatory BP monitoring (ABPM) was measured using a noninvasive, portable, validated recorder (Spacelab 90207; SpaceLabs Medical; Redmond, WA). The patient wore the device for 24 h and was asked to perform daily activities as usual. The monitor was programmed to record BP every 30 min, and data were considered valid if at least 80% of the readings over the 24 h were adequate. A dipping pattern was defined as a reduction in the average systolic and diastolic BP at night > 10% compared to daytime values.^[25] Based on ABPM, hypertension was considered incompletely controlled (incompletely controlled hypertension [ICH]) in patients with systolic BP > 125 mm Hg or diastolic BP > 80 mm Hg at the beginning of the study despite antihypertensive treatment.^[26]

Patients were also evaluated at the Hypertension Unit, Internal Medicine Department to exclude the presence of secondary hypertension. Information about antihypertensive medication, alcohol intake, and cigarette consumption was recorded, and body mass index (BMI) was measured. Daytime sleepiness was assessed using the Epworth sleepiness scale (ESS).

Once the diagnosis of OSA was established and baseline ABPM was measured for a second night, CPAP was titrated. Patients underwent full-night polysomnographic titration at the sleep laboratory. The level of CPAP was increased until respiratory events, snores, and oxygen desaturation were eliminated during all sleep stages in the supine position, so that residual AHI was always

Study Protocol

After the titration night, patients were prescribed CPAP for ambulatory use. Patients were followed up for 24 months and then reevaluated by a new ABPM, ESS, and clinical questionnaire. During this visit, objective compliance with CPAP was assessed by reading the internal time counter of the device.

An attempt was made not to change the antihypertensive medication during the study. Treatment was changed only if a patient had persistent symptomatic hypotension, hypertensive crisis, or target organ involvement secondary to ICH. In these cases, one or more antihypertensive drugs were added or removed, as needed, but the doses of the drugs were not changed. Patients who withdrew treatment with CPAP during follow-up were excluded from the study.

Data Analysis

The primary outcome variable was the change in 24-h mean arterial pressure (24hMAP) with CPAP at the end of the follow-up compared to baseline. Secondary outcome variables included changes in other ABPM parameters, as well as changes in the dipping pattern. In addition, whether the degree of change in 24hMAP correlated with CPAP compliance, OSA severity, or baseline ABPM values, and identification of subgroups of patients in whom CPAP could be more effective were also secondary outcome variables.

Statistical software (version 13.0; SPSS; Chicago, IL) was used for data processing and statistical analysis. Continuous variables are expressed as mean ± SD, and qualitative variables are expressed as percentage. Normal distribution of the variables was confirmed with the Kolmogorov test. Changes in the number of antihypertensive drugs and changes in ABPM after intervention compared to baseline were assessed using a paired t test on an intention-to-treat basis. For the comparison of two qualitative variables with repeated measures, the McNemar test was used. The relationships between CPAP compliance, OSA severity, and baseline ABPM values and the magnitude of change in 24hMAP were assessed by Pearson correlation. Linear regression analysis was performed to elicit if any pretreatment variable was useful to predict significant reductions in 24hMAP after CPAP treatment; p ≤ 0.05 was considered significant.

The sample size was calculated to detect a change of 4 mm Hg in 24hMAP after CPAP treatment compared to baseline. Accordingly, we calculated that at least 50 patients must complete the study if an α error of 0.05 and a power of 0.80 were used.

Results

Seventy patients fulfilled the inclusion criteria, but 4 patients declined to take part in the study (2 patients lived too far away, and 2 patients refused treatment with CPAP). The remaining 66 patients began the study. Seven patients were unavailable for follow-up (three patients could not be contacted, and four patients refused follow-up visits), and four patients withdrew CPAP before the end point and were thus excluded. Finally, 55 patients completed the study. The study sample was similar in terms of age, sex, BMI, daytime sleepiness, sleep apnea severity, number of drugs prescribed, or BP measures to the group of 15 patients who did not finished the study. Baseline characteristics and ABPM of the study sample are shown in Table 1 and Table 2 . At the end of the 24-month follow-up period, compliance with CPAP was 5.3 ± 1.9 h/d. No changes in BMI (35.4 ± 5.8 kg/m² vs 35.5 ± 5.9 kg/m²; p = 0.87), alcohol intake (6.3 ± 11.6 g/d vs 10.1 ± 18.8 g/d; p = 0.09), or cigarette consumption (2.4 ± 5.3 cigarettes per day 3.0 ± 7.1 cigarettes per day; p = 0.52) were observed compared to the baseline. Daytime sleepiness significantly decreased (ESS score, 8.2 ± 3.1 vs 13.4 ± 4.0; p < 0.0005) after treatment with CPAP. During follow-up, antihypertensive treatment was not changed in 40 patients (72.7%), reduced in 10 patients (18.1%), and increased in 5 patients (9.0%) due to inadequate BP control. At the end of the study period, patients were receiving fewer antihypertensive drugs compared to baseline (2.0 ± 1.0 drugs per patient vs 2.2 ± 0.9 drugs per patient; p = 0.04). Cardiovascular events developed in three patients during follow-up: acute coronary syndrome (n = 1), transient ischemic attack (n = 1), and two episodes of transient arrhythmia (atrial fibrillation) [n = 1]. In the first patient, antihypertensive treatment was increased because ICH was detected, while in the other two patients changes were not made because they were compliant with CPAP and BP was adequately controlled.

On an intention-to-treat basis, a significant decrease after CPAP treatment in diastolic BP (- 2.2 mm Hg; 95% confidence interval [CI], - 4.2 to - 0.1 mm Hg; p = 0.03) but not in other ABPM parameters was observed ( Table 3 ). However, a correlation between the magnitude of change in 24hMAP and baseline ABPM (systolic BP, r = - 0.43, p = 0.001; diastolic BP, r = - 0.38, p = 0.004) and hours of use of CPAP (r = - 0.30, p = 0.02) was observed. That is, a decrease in 24hMAP was greater with better CPAP compliance and with higher baseline systolic and diastolic BP. There was no correlation between 24hMAP and OSA severity as measured by the AHI (r = - 0.06, p = 0.62).

When the effect of CPAP was specifically analyzed in a subgroup of 35 patients with ICH at entry, there was a significant decrease in 24hMAP (- 4.4 mm Hg; 95% CI, - 7.9 to - 0.9 mm Hg; p = 0.01) and the rest of the ABPM parameters after treatment with CPAP ( Table 4 ) despite a reduction in the number of antihypertensive drugs (2.2 ± 1.1 drugs per patient vs 2.4 ± 1.0 drugs per patient; p = 0.04). Similarly, in a subgroup of 27 patients with CPAP compliance > 5.3 h/d, 24hMAP (- 5.3 mm Hg; 95% CI, - 9.5 to - 1.2 h/d; p = 0.01) and other ABPM parameters were significantly decreased, compared to baseline ( Table 5 ), without changes in medication (2.1 ± 1.2 drugs per patient vs 2.4 ± 1.0 drugs per patient; p = 0.32).

Only 10 patients (18.2%) had a dipping pattern in the 24-h BP profile at entry, while 45 patients (81.8%) were nondippers. The number of patients with a normal circadian dipping pattern significantly increased (29 patients, 52.7%; vs 10 patients, 18.2%; p = 0.0006) at the end of follow-up. A significant recovery of the dipper pattern was shown irrespective of CPAP compliance or baseline BP control ( Table 6 ). Linear regression analysis showed that baseline systolic BP (ß = - 0.2; 95% CI, - 0.4 to - 0.08; p = 0.004) and hours of CPAP compliance (ß = - 1.1; 95% CI, - 2.3 to - 0.004; p = 0.04) were independent predictors of significant reductions in 24hMAP with CPAP.

Discussion

The results of this study show that long-term CPAP treatment increased the proportion of patients who regained the normal circadian dipping pattern and showed significant reductions in diastolic BP, but only a modest effect on the rest of ABPM parameters in patients with OSA and hypertension undergoing antihypertensive treatment. Most importantly, in the subgroups of patients with good compliance or poorly controlled hypertension at entry, CPAP was especially effective in causing significant reductions in all ABPM parameters. Baseline systolic BP and hours of CPAP were determined to be independent pretreatment predictors of significant reductions in BP with CPAP.

In this prospective trial, the long-term effect of CPAP on ABPM in patients with OSA and hypertension was analyzed. Diagnosis of OSA and CPAP titration were based on full-night, conventional polysomnography, and hypertension was diagnosed according to standard criteria. Furthermore, a follow-up period of 24 months is sufficiently long to show significant changes in BP, and the sample size was calculated to detect BP changes of at least 4 mm Hg. Nevertheless, the study has some deficiencies. A control group of patients was not included because it would have been unethical to withhold effective CPAP treatment for such a long time. Although we tried not to change antihypertensive treatment during follow-up, some patients needed modifications. Treatment medication was increased in 5 patients (hypertensive crisis, n = 4; acute coronary syndrome, n = 1) and decreased in 10 patients due to persistent symptomatic hypotension. Although these changes could confound effects on BP, we suggest that CPAP effects were not overestimated since the intake of antihypertensive drugs decreased (2.0 ± 1.0 drugs per patient vs 2.2 ± 0.9 drugs per patient; p = 0.04) compared to baseline at the end of the study period, without changes in the medication dose.

Several noncontrolled studies have analyzed the long-term effect of CPAP on BP with conflicting results. Moller et al^[24] found a significant improvement in diastolic BP with CPAP that correlated with a decrease in both plasma renin and angiotensin II concentrations in 13 patients (only 3 were hypertensive) followed up for 14 months. Hedner et al^[23] reported that BP and cardiac structure remained unchanged in 12 patients (4 were hypertensive) treated with CPAP for 20 months despite a marked reduction in catecholamine excretion. Sanner et al^[19] reported a significant decrease in mean BP in 69 OSA patients (46 were hypertensive) treated with CPAP for 9 months. Rauscher et al^[22] analyzed 60 hypertensive patients (33 accepted CPAP and 27 refused) for 512 days, and showed that the improvements in BP correlated with changes in BMI but not with CPAP use. Hermida et al^[21] compared 83 and 39 OSA patients with and without CPAP treatment, respectively, for 4 months and found a small but nonsignificant decrease in ABPM in treated compared to nontreated patients. Finally, Narkiewicz et al^[7] compared normotensive patients with (11 patients) and without (9 patients) CPAP treatment and observed a reduction in sympathetic activity but without BP changes in the CPAP group after 12 months.

Our trial differs from the above-mentioned studies because we specifically analyzed a group of hypertensive patients undergoing antihypertensive treatment, we had longest follow-up duration, and our sample size was large enough to show changes in BP. On an intention-to-treat basis, treatment with CPAP increased the proportion of patients who recovered the dipper pattern and significantly decreased diastolic BP but had a modest effect on the rest of ABPM parameters. However, it must be noted that the total number of drugs per patient was reduced during follow-up. Therefore, we cannot exclude that a beneficial effect of CPAP on BP could be offset by a significant decrease in medical antihypertensive treatment during follow-up.

The most interesting finding of our study is the recognition of subgroups of patients for whom CPAP could play an important role on BP control. We have shown a correlation between the changes in 24hMAP and baseline ABPM values: the higher the systolic and diastolic BP at entry, the greater the improvement in 24hMAP with CPAP. Hence, we found that 24hMAP decreased significantly compared to baseline when a subgroup of 35 patients with ICH at entry was analyzed. This improvement applied not only to 24hMAP but to all ABPM parameters, and remarkably these changes occurred despite a significant decrease in the number of antihypertensive drugs used during follow-up. These data suggest that the beneficial effects of CPAP on BP may be more evident in patients with high BP or ICH but be only modestly effective in patients with well-controlled hypertension. However, it cannot be ruled out that the greater decrease in BP in this group merely reflects a regression to mean: patients whose BP was higher to begin with might expect a greater drop in BP than those patients whose BP was within the normal range. Unfortunately, this possible bias cannot be addressed with the experimental design of our trial.

We have also shown a correlation between the changes in 24hMAP and CPAP compliance, with more improvements in BP as CPAP compliance increases. Significant reductions in 24hMAP and all other ABPM parameters after CPAP treatment were observed in a subgroup of 27 patients with objective CPAP use > 5.3 h/d (average compliance of the sample). These results are consistent with previous studies.^[12,27] Finally, we did not find a correlation between OSA severity and changes in 24hMAP. This lack of dose response could be explained because most patients in our study had severe OSA. To support these findings, a linear regression analysis showed that baseline systolic BP and hours of CPAP were independent pretreatment predictors of significant reductions in 24hMAP with CPAP.

The results of the present study are important because a large prospective study^[28] has shown that a 5 mm Hg decrease in diastolic BP may be associated with a 34% stroke and 21% coronary heart disease event-rate risk reduction. Our results show a decrease of 4.2 mm Hg and 4.8 mm Hg in diastolic BP in subgroups of patients with ICH and good CPAP compliance, respectively, and therefore a significant potential reduction in cardiovascular mortality and morbidity should be expected in these patients.

In summary, the present study shows that in hypertensive OSA patients receiving antihypertensive treatment, long-term CPAP treatment improved the dipper pattern and caused significant reductions in diastolic BP but affected other ABPM parameters modestly. However, CPAP treatment was especially effective in causing significant BP reductions in all ABPM parameters in patients with ICH or those with good CPAP compliance. It is therefore suggested that CPAP treatment should be recommended for hypertensive OSA patients, especially for those with high medically controlled hypertension, because beneficial effects are expected if the compliance is good.

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Abbreviation Notes

ABPM = ambulatory BP monitoring; AHI = apnea-hypopnea index; BMI = body mass index; CI = confidence interval; CPAP = continuous positive airway pressure; ESS = Epworth sleepiness scale; ICH = incompletely controlled hypertension; OSA = obstructive sleep apnea; 24hMAP = 24-h mean arterial pressure

Reprint Address

Francisco Campos-Rodriguez, MD, Avda. Emilio Lemos N° 19, Portal 2, 4-E, 41020 Sevilla, Spain; E-mail: fcamposr@telefonica.net .