Abstract
Rationale: Randomized controlled trials (RCTs) have shown that continuous positive airway pressure (CPAP) treatment of obstructive sleep apnea (OSA) reduces blood pressure (BP). CPAP treatment has never been compared with antihypertensive medications in an RCT.
Objectives: To assess the respective efficacy of CPAP and valsartan in reducing BP in hypertensive patients with OSA never treated for either condition.
Methods: In this 8-week randomized controlled crossover trial, 23 hypertensive patients (office systolic BP/diastolic BP: 155 ± 14/102 ± 11 mm Hg) with OSA (age, 57 ± 8 yr; body mass index, 28 ± 5 kg/m2; apnea–hypopnea index, 29 ± 18/h) were randomized first to either CPAP or valsartan (160 mg). The second 8-week period consisted of the alternative treatment (crossover) after a 4-week washout period.
Measurements and Main Results: Office BP and 24-hour BP were measured before and at the end of the two active treatment periods. Twenty-four–hour mean BP was the primary outcome variable. There was an overall significant difference in 24-hour mean BP between treatments: the change in 24-hour mean BP was −2.1 ± 4.9 mm Hg (P < 0.01) with CPAP, and −9.1 ± 7.2 mm Hg with valsartan (P < 0.001), with a difference of −7.0 mm Hg (95% confidence interval, −10.9 to −3.1 mm Hg; P < 0.001). The difference was significant not only during daytime but also during nighttime: the change in nighttime mean BP with CPAP was −1.3 ± 4.6 mm Hg (not significant), and −7.4 ± 8.4 mm Hg with valsartan (P < 0.001), with a difference of −6.1 mm Hg (P < 0.05) (95% confidence interval, −10.8 to −1.4 mm Hg).
Conclusions: In an RCT, although the BP decrease was significant with CPAP treatment, valsartan induced a fourfold higher decrease in mean 24-hour BP than CPAP in untreated hypertensive patients with OSA.
Clinical trial registered with www.clinicaltrials.gov (NCT00409487).
Randomized controlled trials (RCTs) have demonstrated that continuous positive airway pressure (CPAP) reduces the 24-hour mean blood pressure in patients with obstructive sleep apnea (OSA). Albeit significant in terms of cardiovascular risk reduction, this effect is limited compared with that obtained by standard antihypertensive drugs in patients with essential hypertension.
Until this study, there has been no direct comparison between CPAP and antihypertensive medications. In an RCT, although the blood pressure (BP) decrease was significant on CPAP treatment, valsartan induced a fourfold greater decrease in 24-hour mean BP than CPAP in untreated hypertensive patients with OSA. The combined effect of both therapies on blood pressure control might be additive.
Several randomized controlled trials (RCTs) have demonstrated that continuous positive airway pressure (CPAP), the first-line therapy for moderate to severe sleep apnea, reduces the 24-hour mean blood pressure by a pooled estimated effect of approximately −2 mm Hg (4–6). Albeit significant in terms of reduction of cardiovascular risk, this effect is limited compared with BP reduction obtained with standard antihypertensive drugs in patients with essential hypertension. However, until now, there has been no direct comparison between CPAP and antihypertensive medications. In addition, none of the current hypertension guidelines provides specific guidance for the use of antihypertensive agents in the treatment of hypertensive patients with OSA (7). In rats subjected to intermittent hypoxia (IH), the angiotensin II receptor blocker losartan, acting through inhibition of the RAS, suppresses the BP increase usually associated with IH exposure (2, 8). β-Blockers, by reducing sympathetic activity, represent another logical choice for hypertensive patients with OSA. Only one study has compared four classes of antihypertensive drugs in OSA and suggested that β-blockers were the most effective drug in terms of BP reduction (9). However, sleep apnea is associated with an increased risk for insulin resistance, type 2 diabetes, and metabolic syndrome (10). Large-scale clinical studies have reported a significant reduction in type 2 diabetes incidence in hypertensive patients treated with angiotensin II receptor antagonists compared with those taking β-blockers (11, 12). For all these reasons, specific and selective angiotensin II receptor blockers, such as valsartan, could be the first-line treatment for hypertensive patients with sleep apnea.
Antihypertensive treatments do not easily normalize blood pressure in patients with OSA. On the other hand, the specific effect of CPAP on blood pressure in hypertensive patients with OSA is difficult to interpret because of interference by the usual concomitant antihypertensive therapy. Our hypothesis is that in patients with OSA with no prior treatment involving CPAP and hypertensive agents, the effect of treatment is greater for valsartan and the combination of valsartan plus CPAP will provide an additive effect compared with either therapy alone. Surprisingly, no RCT studies are available comparing CPAP treatment with antihypertensive medications. Moreover, the potential additive effect of combined treatments has never been prospectively evaluated.
Consequently, we conducted a randomized controlled crossover trial to compare the effects of CPAP and valsartan (160 mg orally) on blood pressure in hypertensive patients with OSA never treated for either condition. Patients whose BP remained uncontrolled by CPAP or valsartan alone at the end of the RCT continued in a 8-week open label study with a combination of CPAP and valsartan.
Some of the results of this study have been previously reported in the form of abstracts.
A complete detailed description of methods is available in the online supplement. Regarding the analysis and the presentation of the trial, we followed the “Revised CONSORT Statement for Reporting Randomized Trials.”
Patients (>18 yr) with OSA (apnea–hypopnea index [AHI] > 15/h) and hypertension (office systolic and/or diastolic BP ≥140 and 90 mm Hg, respectively), naive of any treatment (CPAP and antihypertensive drug), were included in this crossover randomized controlled trial for two periods of 8 weeks to either CPAP or valsartan (160 mg) separated by a 4-week washout period.
Twenty-four–hour mean BP was the primary outcome variable assessed by 24-hour ambulatory BP monitoring (ABPM), before and at the end of the two active treatment periods.
Patients whose BP remained uncontrolled by CPAP or valsartan alone continued on to an open label 8-week study with a combination of CPAP and valsartan.
Patients were excluded if they had respiratory failure, declined to participate, or were unable to give informed consent. The study was approved by the Ethics Committee of Grenoble University Hospital (Grenoble, France). All patients signed a written informed consent form.
A detailed description of materials and methods of scoring is provided in the online supplement.
Effective CPAP was generated with the same automatic CPAP machine models (SOMNOsmart 2; Weinmann, Hamburg, Germany) for all patients. While part the drug treatment arm, patients ingested a single daily tablet of valsartan (160 mg), an orally active specific and selective angiotensin II receptor blocker, on awakening from nighttime sleep. CPAP compliance and residual AHI were measured from the machine's internal microprocessor. Treatment compliance with valsartan was assessed by tablet count at the end of the treatment period.
The following clinical parameters were assessed at each time point of the study: systolic BP (SBP), diastolic BP (DBP), mean BP (MBP), and heart rate. Office BP measurement and clinic hypertension definition were in agreement with European Society of Hypertension–European Society of Cardiology guidelines (13).
ABPM was performed with a Spacelabs 90207 device (Spacelabs Healthcare, Redmond, WA). Measurements were made every 15 minutes over 24 hours. The following ABPM parameters were studied: mean SBP, DBP, and MBP over the 24 hours and over daytime (07:00 to 22:00) and nighttime (22:00 to 07:00).
All subjects had measurements of total plasma cholesterol (enzymatic colorimetry; normal, 1.79–2.73 g/L), triglycerides (enzymatic colorimetry; normal, 0.56–2.28 g/L), high-density lipoprotein cholesterol (enzymatic colorimetry, normal, 0.39–0.63 g/L), low-density lipoprotein cholesterol (Friedewald formula; normal, 1.01–1.81 g/L), glucose (enzymatic method; normal, 3.8–5.8 mmol/L), and creatinine (enzymatic colorimetry; normal, 62–106 mmol/L).
A detailed description of the sample size calculation method and of data analysis is provided in the online supplement.
Continuous data are presented as means ± SD (or as means and 95% confidence interval for the difference between the two treatments). Categorical data are expressed as percentages. Normality was assessed using skewness and Kurtosis tests. A treatment effect test (adjusted for period), a period effect test (adjusted for treatment), and a test for the interaction between treatment and period were successively used to assess respective effect of treatments, treatment sequence, and the first-order carryover risk. This allowed taking into account the incomplete return to baseline for some of the BP values after the 4-week washout periods. No significant interaction was found between treatment and period. Significance was set as P ≤ 0.05.
The trial design is shown in Figure 1. Twenty-eight patients were randomized and Table 1 shows their characteristics at inclusion. Patients were mainly male with moderate obesity and had moderate to severe obstructive sleep apnea syndrome. The subgroup treated by CPAP first was significantly younger. Office blood pressure (BP) was clearly abnormal with systolic BP and diastolic BP of 155 ± 14 and 102 ± 11 mm Hg, respectively. Thirteen percent of patients were treated for dyslipidemia; none suffered from diabetes or cardiovascular disease other than hypertension.
Figure 1. Trial design. BP = blood pressure; CPAP = continuous positive airway pressure; RCT = randomized controlled trial.
[More] [Minimize]All Patients | Valsartan First | CPAP First | |
|---|---|---|---|
| Age, yr | 57 ± 8 | 60 ± 6 | 54 ± 9* |
| Body mass index, kg/m2 | 28.2 ± 5.0 | 28.1 ± 4.7 | 28.3 ± 5.6 |
| Sex, male (%) | 82.6 | 83.3 | 81.8 |
| Epworth Sleepiness Scale score | 10.0 ± 4.2 | 8.7 ± 4.8 | 11.5 ± 2.9 |
| AHI, no./h | 29.0 ± 17.6 | 29.3 ± 16.0 | 28.7 ± 20.1 |
| Mean nocturnal SpO2, % | 93.7 ± 1.9 | 93.7 ± 2.4 | 93.7 ± 1.4 |
| Nadir nocturnal SpO2, % | 82.5 ± 5.8 | 81.2 ± 4.9 | 83.9 ± 6.5 |
| Sleep time spent with SpO2 < 90%, % | 7.7 ± 18.8 | 12.0 ± 25.5 | 2.9 ± 3.5 |
| Office SPB, mm Hg | 154.9 ± 14.1 | 155.3 ± 15.3 | 154.4 ± 13.3 |
| Office DBP, mm Hg | 102.2 ± 11.2 | 100.9 ± 13.4 | 103.5 ± 8.6 |
| Office MBP, mm Hg | 119.7 ± 10.5 | 119.1 ± 12.2 | 120.5 ± 8.7 |
| HDL cholesterol, g/L | 0.60 ± 0.21 | 0.55 ± 0.15 | 0.65 ± 0.26 |
| LDL cholesterol, g/L | 1.33 ± 0.25 | 1.35 ± 0.27 | 1.30 ± 0.21 |
| Total cholesterol, g/L | 2.12 ± 0.31 | 2.11 ± 0.37 | 2.15 ± 0.23 |
| Triglycerides, g/L | 1.01 ± 0.34 | 1.02 ± 0.34 | 0.99 ± 0.34 |
| hs-CRP, mg/L | 2.8 ± 7.3 | 4.1 ± 9.8 | 1.1 ± 0.5 |
| Fasting glucose, mmol/L | 5.3 ± 0.6 | 5.3 ± 0.5 | 5.3 ± 0.7 |
The mean effective CPAP pressure was 8 ± 1 cm H2O and the mean compliance with the device was 4.8 ± 2.1 hours per night. Residual AHI on CPAP was in the normal range, at 3.3 ± 2.9/hour of recording.
Table 2 and Figure 2 show 24-hour blood pressure data for the intention-to-treat analysis. Overall, BP changes were greater with valsartan for all BP parameters (Table 2). The change in 24-hour mean BP on CPAP from baseline was −2.1 ± 4.9 mm Hg (P < 0.01). The other significant changes associated with CPAP treatment were significant reductions in daytime and 24-hour diastolic BP values. Decreases in BP were greater with valsartan and were significant for all BP parameters, with a reduction of 9.1 ± 7.2 mm Hg in 24-hour mean BP while taking valsartan (P < 0.001). A difference of −7.0 mm Hg (95% confidence interval [CI], −10.9 to −3.1 mm Hg; P < 0.001) was found between valsartan and CPAP for 24-hour mean BP. Noticeably, the difference was significant not only during daytime but also during nighttime: the change in nighttime 24-hour BP was −1.3 ± 4.6 mm Hg (not significant) with CPAP, and −7.4 ± 8.4 mm Hg with valsartan (P < 0.001), with a difference of −6.1 mm Hg (P < 0.05) (95% CI, −10.8 to –1.4 mm Hg).
Figure 2. Ambulatory blood pressure profile of patients receiving valsartan or continuous positive airway pressure (CPAP) in the intention-to-treat analysis. DBP = diastolic blood pressure; SBP = systolic blood pressure.
[More] [Minimize]Valsartan | CPAP | |||||||
|---|---|---|---|---|---|---|---|---|
| Before | After | Before | After | Difference in BP Change* | P Value† | |||
| 24-h SBP, mm Hg | 139.1 ± 9.2 | 128.5 ± 10.9‡ | 138.6 ± 9.7 | 136.9 ± 13.2 | −8.90 (−14.0 to −3.9) | <0.001 | ||
| 24-h DBP, mm Hg | 87.7 ± 8.6 | 79.3 ± 8.4‡ | 87.3 ± 8.9 | 85.0 ± 10.4§ | −6.04 (−9.5 to −2.6) | 0.002 | ||
| 24-h MBP, mm Hg | 104.8 ± 8.1 | 95.7 ± 8.5‡ | 104.4 ± 8.5 | 102.3 ± 10.9§ | −7.00 (−10.9 to −3.1) | <0.001 | ||
| Daytime SBP, mm Hg | 144.8 ± 10.4 | 133.0 ± 12.5‡ | 144.4 ± 10.3 | 142.6 ± 15.5 | −9.96 (−15.8 to −4.1) | <0.001 | ||
| Daytime DBP, mm Hg | 92.4 ± 10.2 | 83.4 ± 9.1‡ | 92.6 ± 9.7 | 89.8 ± 12.0§ | −6.17 (−9.9 to −2.4) | 0.002 | ||
| Daytime MBP, mm Hg | 109.9 ± 9.6 | 99.9 ± 9.6‡ | 109.8 ± 9.1 | 107.4 ± 12.7 | −7.43 (−11.7 to −3.1) | 0.001 | ||
| Nighttime SBP, mm Hg | 128.1 ± 9.2 | 119.5 ± 9.8‡ | 127.3 ± 10.9 | 126.3 ± 11.5 | −7.70 (−13.1 to −2.3) | 0.009 | ||
| Nighttime DPB, mm Hg | 78.3 ± 7.7 | 71.4 ± 8.4§ | 77.2 ± 8.5 | 75.6 ± 8.7 | −5.26 (−9.8 to −0.8) | 0.020 | ||
| Nighttime MBP, mm Hg | 94.9 ± 7.5 | 87.5 ± 8.4‡ | 93.9 ± 8.9 | 92.5 ± 9.3 | −6.07 (−10.8 to −1.4) | 0.010 | ||
| 24-h heart rate, bpm | 78.0 ± 9.1 | 75.7 ± 6.7‖ | 77.8 ± 8.2 | 75.7 ± 8.8 | −0.51 (−7.6 to 6.6) | 0.88 | ||
In the per-protocol analysis, patients with poor CPAP compliance (compliance, <3 h per night) were excluded. All patients complied with valsartan treatment (minimal compliance, 85% of the tablets; median, 100%). BP changes with CPAP became significant for all parameters except daytime systolic blood pressure (Table 3). The valsartan-induced reductions in BP remained significantly greater than those induced by CPAP, except for nighttime values, for which only a trend was observed. There was a significant correlation between the improvement in nighttime BP and the duration of CPAP use (r = −0.43, P < 0.04) (Figure 3).
Figure 3. Significant correlation between the improvement in nighttime blood pressure (BP) and the duration of continuous positive airway pressure (CPAP) use (r = −0.43, P < 0.04).
[More] [Minimize]Valsartan | CPAP | |||||||
|---|---|---|---|---|---|---|---|---|
| Before | After | Before | After | Difference in BP Change* | P Value† | |||
| 24-h SBP, mm Hg | 138.3 ± 7.1 | 127.3 ± 7.5‡ | 137.5 ± 8.4 | 134.3 ± 9.1§ | −7.83 (−14.2 to −1.5) | 0.016 | ||
| 24-h DBP, mm Hg | 86.7 ± 8.6 | 78.8 ± 7.4‡ | 86.3 ± 8.9 | 83.3 ± 9.3‖ | −5.00 (−9.2 to −0.8) | 0.028 | ||
| 24-h MBP, mm Hg | 103.9 ± 7.3 | 94.9 ± 6.6‡ | 103.4 ± 8.0 | 100.3 ± 8.8‖ | −5.94 (−10.7 to −1.2) | 0.019 | ||
| Daytime SBP, mm Hg | 143.9 ± 8.0 | 131.2 ± 7.5‡ | 142.9 ± 8.3 | 139.9 ± 10.4 | −9.67 (−17.0 to −2.3) | 0.008 | ||
| Daytime DBP, mm Hg | 91.4 ± 10.2 | 82.5 ± 7.4‡ | 91.3 ± 9.4 | 87.9 ± 10.7‖ | −5.50 (−9.9 to −1.1) | 0.016 | ||
| Daytime MBP, mm Hg | 108.9 ± 8.7 | 98.7 ± 6.4‡ | 108.5 ± 8.1 | 105.3 ± 10.1§ | −6.89 (−12.2 to −1.6) | 0.013 | ||
| Nighttime SBP, mm Hg | 127.4 ± 7.6 | 119.4 ± 9.1‖ | 126.6 ± 10.2 | 124 ± 9.3§ | −5.5 (−12.0 to 1.0) | 0.11 | ||
| Nighttime DPB, mm Hg | 77.3 ± 7.3 | 71.7 ± 8.7‖ | 76.4 ± 8.8 | 74.3 ± 8.1§ | −3.50 (−8.9 to 1.9) | 0.18 | ||
| Nighttime MBP, mm Hg | 94.0 ± 6.5 | 87.6 ± 8.2‖ | 93.1 ± 8.8 | 90.9 ± 8.1§ | −4.17 (−9.7 to 1.4) | 0.16 | ||
| 24-h heart rate, bpm | 77.9 ± 10.1 | 75.6 ± 7.4 | 77.3 ± 8.9 | 75.3 ± 9.4 | −0.45 (−9.6 to 8.7) | 0.92 | ||
In those patients whose BP remained uncontrolled by CPAP alone or valsartan alone, the follow-up open study with the use of CPAP and valsartan in combination demonstrated significant additive effects of the two treatments on blood pressure values (Table 4 and Figure 4). As Figure 4 clearly illustrates, the difference was particularly noticeable during nighttime. However, the benefit of CPAP plus valsartan compared with valsartan alone was only significant for office BP and not for 24-hour BP measurement.
Figure 4. Open continuing study: Ambulatory blood pressure profile of patients receiving valsartan, continuous positive airway pressure (CPAP), or a combination of both. DBP = diastolic blood pressure; SBP = systolic blood pressure.
[More] [Minimize]Valsartan | CPAP | Valsartan + CPAP | P Value* | |
|---|---|---|---|---|
| Office SPB, mm Hg | 145.8 ± 13.7 | 147.5 ± 15.1 | 131.0 ± 9.2†‡ | 0.002 |
| Office DBP, mm Hg | 98.5 ± 9.4 | 95.7 ± 10.6 | 87.8 ± 8.8†‡ | 0.013 |
| Office MBP, mm Hg | 114.3 ± 9.8 | 113.0 ± 10.9 | 102.2 ± 7.2†‡ | 0.017 |
| 24-h SBP, mm Hg | 128.5 ± 7.0 | 136.5 ± 7.8 | 124.5 ± 7.8‡ | 0.005 |
| 24-h DBP, mm Hg | 79.5 ± 7.5‡ | 85.2 ± 10.1 | 77.9 ± 9.2‡ | 0.005 |
| 24-h MBP, mm Hg | 95.8 ± 6.0 | 102.3 ± 8.8 | 93.4 ± 7.6‡ | 0.005 |
| Daytime SBP, mm Hg | 132.0 ± 7.7 | 142.0 ± 10.8 | 129.8 ± 9.4‡ | 0.013 |
| Daytime DBP, mm Hg | 82.8 ± 7.5‡ | 89.8 ± 12.6 | 82.0 ± 10.9‡ | 0.006 |
| Daytime MBP, mm Hg | 99.2 ± 6.0 | 107.2 ± 11.3 | 97.9 ± 9.3‡ | 0.009 |
| Nighttime SBP, mm Hg | 121.3 ± 8.8 | 126.0 ± 6.4 | 115.7 ± 8.7‡ | 0.009 |
| Nighttime DPB, mm Hg | 73.3 ± 9.0 | 76.1 ± 7.1 | 69.9 ± 7.6‡ | 0.047 |
| Nighttime MBP, mm Hg | 89.3 ± 8.2 | 92.7 ± 6.1 | 85.2 ± 7.1‡ | 0.022 |
| 24-h heart rate, bpm | 77.9 ± 7.6 | 77.6 ± 8.9 | 76.6 ± 7.1 | 0.59 |
This study is the first randomized controlled trial directly comparing the effects of CPAP and an antihypertensive drug in a group of hypertensive patients with sleep apnea, never treated for either condition. Although the reduction in blood pressure was significant under CPAP, the angiotensin II receptor blocker valsartan induced a fourfold greater reduction in 24-hour mean BP. During nighttime, when respiratory events were acutely suppressed only by CPAP, the reduction in blood pressure was still significantly greater with valsartan. When used in combination, the two treatments appeared to have significant additive effects on blood pressure. This was true for office BP; there was only a trend for nighttime BP.
Patients included in the study were slightly obese with moderate to severe OSA and used CPAP with a mean compliance of 4.8 hours per night. The change in 24-hour mean BP with CPAP was −2.1 ± 4.9 mm Hg, which is in accordance with the results of several meta-analyses (4–6). In the meta-analysis by Haentjens and colleagues (4), the pooled estimate of the effect of CPAP intervention was −1.69 mm Hg for 24-hour mean BP (95% CI, −2.69 to −0.69 mm Hg). A strength of our work compared with previous studies (see review by Duran-Cantolla and colleagues [14]) is to have included only patients with newly diagnosed OSA with hypertension, who had never been treated for either condition. In studies evaluating the ability of CPAP to reduce blood pressure, treatment duration varies widely, ranging from two weeks to 1 year. In a multicenter controlled trial involving 359 nonsleepy hypertensive patients with OSA reported by Barbe and colleagues, BP reduction was small but significant at 1 year whereas at 3 months changes in blood pressure were similar in the control and CPAP groups (15). This study was completed in a particular subgroup of nonsleepy patients with about 50% of the subjects taking antihypertensive drugs. However, the results suggest that the 8-week CPAP application during our study might have underestimated long-term CPAP efficacy on blood pressure. In unselected OSA populations, however, reductions in BP of comparable magnitude have been observed during similar or shorter follow-up periods.
Intermittent hypoxia (IH) is known to activate the rennin–angiotensin system (RAS) and could be implicated in OSA-related hypertension. Angiotensin II (AT1) receptors are also located on presynaptic terminals of peripheral sympathetic neurons. These AT1 receptors are involved in the regulation of sympathetic nerve activity, which is clearly elevated in patients with sleep apnea. Heightened sympathetic activity might also occur via angiotensin II facilitation at sympathetic synapses (8). In our study, valsartan treatment was associated with a significant reduction in 24-hour heart rate (Table 2). This suggested a sympatholytic effect of valsartan in the context of OSA. In patients with OSA, the plasma concentration of angiotensin II is elevated (16, 17). Results regarding the vasoconstriction response to angiotensin II are contradictory. Some studies have reported that this response is elevated (18) whereas other data issued from animals exposed to IH failed to demonstrate an increase in angiotensin II–mediated vasoconstriction (19). In rats exposed to IH for 35 days, Fletcher and colleagues showed that RAS blockade with losartan prevented the IH-induced rise in BP (2). The present data, by demonstrating a marked effect of valsartan in reducing BP in patients with OSA, strongly support RAS overactivity as a key mechanism for hypertension in these patients.
First, CPAP is a cumbersome treatment, with 15% initial refusals and 20 to 25% of patients with OSA discontinuing use of the device over years. Sleep apnea is more and more frequently diagnosed in “at-risk populations” such as in patients with diabetes mellitus (20) or cardiac failure (21). These patient subgroups usually do not complain about sleep apnea symptoms (22, 23) and thus compliance with CPAP is often limited. If left untreated, however, these subjects are likely to be at high risk of mortality (24). Our study suggests that in patients with poor CPAP compliance or who refuse CPAP treatment, angiotensin II receptor blockers may reduce blood pressure more potently than CPAP. This is a strong rationale to propose a risk reduction strategy in these patients, including drugs in association with lifestyle counseling.
Second, CPAP indication is still debated in hypertensive OSA without daytime sleepiness (14). CPAP seems to be even less effective in reducing BP in these patients (25), although not confirmed in the more recent study by Barbé and colleagues (15). The effect obtained with the drug tested in this study is highly significant in terms of reduction in cardiovascular and cerebrovascular risk and, consequently, in risk of death. Accordingly, a drug treatment with none of the drawbacks of CPAP treatment should be considered for patients with severe OSA syndrome and hypertension in the absence of OSA symptoms. Also, patients refusing CPAP or unable to tolerate CPAP on a long-term basis may benefit from such a treatment. This needs to be further tested in this specific subgroup.
Last, 11 of 18 of the CPAP compliers (61%) were insufficiently treated on a 24-hour basis by only one of the evaluated treatments. The combination of CPAP and valsartan in the selected group of patients not controlled by either therapy led to a significant and synergistic reduction in blood pressure. Importantly, despite an optimal medical therapy for BP control, there was a significant drop in all BP measurements when CPAP was added (Table 4). This was true mainly for office BP, with also a tendency for nighttime BP. When limiting the analysis to the subgroup of patients with severe OSA with CPAP compliance greater than 5 hours per night (n = 9; data not shown), the difference remained obvious during daytime between valsartan and CPAP but was less marked during sleep. This was in accordance with the open study, during which the positive effect of combined therapy occurred mainly during night (Figure 4). As persistent high blood pressure at night is associated with poor cardiovascular outcome (26), a treatment association should be considered when elevated nighttime BP is documented by 24-hour blood pressure monitoring. The combination of CPAP and valsartan in the selected group of patients who were not controlled on either therapy led to a significant and synergistic reduction in blood pressure. Our data provide a strong rationale for proposing an association between angiotensin II receptor antagonists and CPAP in the management of hypertensive patients with OSA who do not respond to CPAP alone. These results underline the need to design RCTs specifically targeted to this subgroup of hypertensive patients with OSA uncontrolled by CPAP in terms of BP. Last, the present study suggests that in the subgroup of patients in whom hypertension is still uncontrolled by specific antihypertensive medication, CPAP treatment has an additional beneficial effect on blood pressure. In term of mechanisms, the fact that CPAP and valsartan had additive effects suggests different modalities of action that require further evaluation.
In patients with OSA, the effect of CPAP treatment extends beyond blood pressure control (improvement of vigilance, cognitive function, mood, endothelial function, glucose metabolism, etc.). The importance of CPAP in terms of cardiovascular risk reduction is likely to differ between patients (e.g., presence vs. absence of sleepiness, corisk factors, overt cardiovascular disease) (14). Sleep apnea treatment must now be tailored for each patient, based on metabolic and cardiovascular risks and the willingness of patients to comply with specific requirements (i.e., using CPAP or not, medications, exercise, weight loss, etc.) (27). Important additive effects may be gained by combination of CPAP with antihypertensive treatments.
The authors thank Nathalie Arnol for support in the statistical analysis; clinical research assistants Marie Peeters, Hélène Pierre, and Nouria Elaidi for logistic support; and Lilia Chorfa for technical assistance in medication delivery.
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