In the Literature Resistant Hypertension in Obstructive Sleep Apnea: Is Continuous Positive Airway Pressure the Next Step? Commentary on Martı´nez-Garcia MA, Capote F, Campos-Rodrı´guez F, et al; for the Spanish Sleep Network. Effect of CPAP on blood pressure in patients with obstructive sleep apnea and resistant hypertension: the HIPARCO randomized clinical trial. JAMA. 2013;310(22):2407-2415.

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esistant hypertension, defined as inadequate control of blood pressure (BP) despite treatment with at least 3 antihypertensive medications, poses a significant risk for adverse cardiovascular events and mortality1 and for increased risk of endstage renal disease.2 Consequently, recognizing and treating secondary causes of hypertension in patients with resistant hypertension may help control BP and reduce cardiovascular and kidney disease. One potential secondary cause is obstructive sleep apnea (OSA), which is reported to be present in .70% of patients with resistant hypertension.3,4 OSA is characterized by intermittent narrowing or collapse of the upper airway, leading to periods of hypoxia and hypercapnia that are terminated by cortical or subcortical arousal. It is well demonstrated that OSA results in sympathetic nervous system activation, elevated adrenergic tone, and endothelial dysfunction, thus contributing to resistant hypertension.5 A recent meta-analysis involving 32 studies and about 2,000 patients affirmed that using continuous positive airway pressure (CPAP) for treating OSA provides modest reductions in BP by 2-3 mm Hg on average.6 Similar beneficial effects on BP are seen when OSA is treated with an oral appliance, particularly in patients with pre-existing hypertension and/or more severe OSA.7-9 These studies provide compelling evidence that improvements in BP in certain OSA patient subgroups are related to OSA treatment rather than the specific therapeutic modality per se. However, what remains uncertain are which OSA subgroups are most likely to achieve better BP control when the sleep disorder is treated effectively. In this regard, the entity of resistant hypertension is of particular interest to nephrologists.

WHAT DOES THIS IMPORTANT STUDY SHOW? A recent publication by Martínez-Garcia et al10 in JAMA explored the effect of CPAP on BP in patients with OSA and resistant hypertension in the HIPARCO (Hipertensión Arterial Resistente Control con CPAP) trial. This randomized controlled trial from the Spanish Sleep Network recruited patients aged 18-75 years with resistant hypertension from the hypertension clinical units of 24 hospitals in Spain. All participants underwent respiratory polygraphy (American Academy of Sleep Medicine type III technology) at a Am J Kidney Dis. 2014;-(-):---

sleep laboratory, and those with at least moderate OSA (apnea-hypopnea index [AHI] $ 15) underwent 24-hour ambulatory BP monitoring (ABPM) to ascertain the presence of resistant hypertension, defined as average systolic BP $ 130 mm Hg, average diastolic BP $ 80 mm Hg, or both despite concurrent use of at least 3 antihypertensive medications at optimal doses, including a diuretic. Then, 194 patients (mean age, 56 years; 69% men; mean body mass index, 34 kg/m2) were randomly assigned to either CPAP (n 5 98) or no therapy (n 5 96) and followed up for 12 weeks. At baseline, mean AHI was 40.4 6 18.9 and 24-hour mean BP was 103.4 6 9.6 mm Hg. The authors found that the CPAP group had a significant decrease in 24-hour mean BP (3.1 mm Hg; 95% confidence interval [CI], 0.6-5.6; P 5 0.02) and 24-hour diastolic BP (3.2 mm Hg; 95% CI, 1.0-5.4; P 5 0.005), but there was only a trend for improvement in 24-hour systolic BP (3.1 mm Hg; 95% CI, 20.6 to 6.7; P 5 0.10) compared to the control group. These findings did not change even after adjusting for potential confounders, including baseline BP, AHI, Epworth Sleepiness Scale score, nocturnal BP pattern, and prior cardiovascular events. Additionally, CPAP resulted in recovery of a dipping pattern in nocturnal BP, and after 12 weeks of follow-up, more patients in the CPAP group (35.9%) displayed a dipping pattern compared to the control group (21.6%; adjusted odds ratio, 2.4; 95% CI, 1.2-5.1; P 5 0.02). There also was a significant positive correlation between hours of CPAP use and decrease in 24-hour mean BP (r 5 0.29; P 5 0.006), systolic BP (r 5 0.25; P 5 0.02), and diastolic BP (r 5 0.30; P 5 0.005). The authors conclude that there is a clinically and statistically significant reduction in both 24-hour mean BP and diastolic BP with CPAP use in patients with resistant hypertension and moderate to severe OSA. Although exciting, results of this study must be interpreted with some caution. A substantial proportion of patients with a diagnosis of resistant hypertension may have pseudo-resistant hypertension due

Address correspondence to Mark Unruh, MD, University of New Mexico School of Medicine, MSC 10-5550, 1 University of New Mexico, Albuquerque, NM 87131-0001. E-mail: mlunruh@ salud.unm.edu Ó 2014 by the National Kidney Foundation, Inc. 0272-6386/$36.00 http://dx.doi.org/10.1053/j.ajkd.2014.03.008 1

Jhamb, Brown, and Unruh

to medication nonadherence. Although the present study frequently assessed medication adherence using self-reports, it lacked a run-in period prior to randomization and there was no objective measure of adherence, both of which may be important limiting factors. As an example, in a similar study by Pedrosa et al11 of CPAP use in individuals with resistant hypertension, 20% (48 of 243) of patients initially thought to have resistant hypertension had normal BPs after a 2-month run-in period. Second, .90% of the patients with resistant hypertension screened in this study had at least moderately severe OSA, which may be higher than in previous reports.12 A possible explanation for the high degree of OSA severity in the people recruited for the present study may be that the sample was drawn from hypertension clinics and the patients already had been ruled out for other secondary causes of hypertension. Third, the use of ABPM as the primary outcome makes the clinical application of these findings a little less clear. Physicians often focus on an office BP and more often than not on systolic BP, which has only a moderate correlation with mean arterial pressure from ABPM.13,14 Last, because this study was conducted in Spain, the results may not be applicable to other high-risk populations, such as African Americans, due to genetic and environmental differences.

dipping, suggesting that ABPM technology was not at fault. Perhaps there are mechanistic explanations for these counterintuitive results that will emerge in future studies. A novel and interesting hypothesis to explain the benefits of CPAP in this setting could be the role of immune activation in OSA and resistant hypertension. Recurrent intermittent hypoxia in OSA is known to cause oxidative stress, endothelial dysfunction, metabolic dysregulation, sympathetic activation, and systemic inflammation.12 All or some of these factors could lead to vascular remodeling, atherosclerosis, and hypertension in this already at-risk, frequently obese population. Is it possible that effective OSA treatment exerts its BP-lowering effects by improving systemic inflammation? A recent meta-analysis of almost 2,000 patients with OSA concluded that regular CPAP use resulted in a significant decrease in levels of proinflammatory cytokines, including C-reactive protein and interleukin 6.19 Future studies investigating the associations between proinflammatory cytokines, resistant hypertension, and effective treatment of OSA are needed to delineate underlying mechanistic pathways.

HOW DOES THIS STUDY COMPARE WITH PRIOR STUDIES?

Despite its limitations, results of this large multicenter study have important clinical and research implications, although more research is warranted to assess long-term health outcomes of CPAP use on cardiovascular events and mortality. One of the biggest challenges for this kind of research continues to be patient acceptance of CPAP therapy over longer periods. The present study was remarkable in achieving .70% adherence to at least 4 hours of CPAP use per night. A recent meta-analysis reported that patients subjectively prefer autotitrating CPAP over fixed CPAP and demonstrate increased adherence with this modality,20 although other comprehensive meta-analyses have questioned the clinical significance of such findings.21,22 Future studies using autotitrating CPAP over long periods in patients with hypertension (resistant or not) may be needed to assess whether this modality is of greater benefit in such populations. Last, treatment trials in patients with chronic kidney disease (CKD) would help better inform the care provided by nephrologists to these individuals. We have found that OSA has been related to resistant hypertension in patients with both CKD and kidney failure.23 Whether this association is due to OSA exacerbating hypertension or shared risk factors remains to be tested. The use of CPAP to treat resistant hypertension in patients with CKD is attractive given the high burden of medications and the propensity for nondipping in this population.

This study offers the most convincing evidence to date showing CPAP to have a beneficial BP-lowering effect in patients with resistant hypertension and OSA. Limited data from prior observational studies15 and prospective trials11,16-18 indicate that clinically significant BP reductions can be attained when there is good adherence to CPAP treatment. As mentioned, the only other randomized trial specifically evaluating the effect of CPAP in resistant hypertension was conducted by Pedrosa et al,11 who randomly assigned 40 patients to CPAP versus no CPAP. After 6 months of follow-up, CPAP therapy promoted a significant mean reduction of 6.5 mm Hg for daytime systolic BP and 4.5 mm Hg for daytime diastolic BP.11 In a post hoc analysis of another prospective trial by Lozano et al,17 3 months of CPAP use in a subgroup of 41 patients with resistant hypertension showed that this treatment resulted in a significant reduction in 24-hour diastolic BP (24.9 mm Hg). Interestingly, consistent with results of the present study, neither of these previous studies showed a beneficial effect on nocturnal BP. One would hypothesize that CPAP use would reduce arousals from OSA, dampening the recurrent sympathetic nervous stimulation and adrenergic surge at night and thus improving nocturnal BP. Both Pedrosa et al11 and Lozanao et al17 used ABPM to identify nocturnal 2

WHAT SHOULD CLINICIANS AND RESEARCHERS DO?

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In the Literature

In conclusion, clinicians should have a high index of suspicion for OSA in patients with resistant hypertension. Individuals with OSA and resistant hypertension may derive significant benefits in terms of cerebrovascular and cardiovascular protection from regular CPAP use (or perhaps from other OSA treatment modalities), although the reduction in BP may be modest. Future large-scale trials are needed to assess the generalizability of these findings, particularly to different ethnic and racial groups, and evaluate the long-term impact of CPAP use on health outcomes and the extent to which this approach may be used in patients with CKD. Manisha Jhamb, MD, MPH University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania Lee K. Brown, MD Mark Unruh, MD, MS University of New Mexico School of Medicine Albuquerque, New Mexico

REFERENCES 1. Smith SM, Gong Y, Handberg E, et al. Predictors and outcomes of resistant hypertension among patients with coronary artery disease and hypertension. J Hypertens. 2014;32(3):635-643. 2. Tanner RM, Calhoun DA, Bell EK, et al. Incident ESRD and treatment-resistant hypertension: the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study. Am J Kidney Dis. 2014;63(5):781-788. 3. Pedrosa RP, Drager LF, Gonzaga CC, et al. Obstructive sleep apnea: the most common secondary cause of hypertension associated with resistant hypertension. Hypertension. 2011;58(5):811-817. 4. Goncalves SC, Martinez D, Gus M, et al. Obstructive sleep apnea and resistant hypertension: a case-control study. Chest. 2007;132(6):1858-1862. 5. Marcus JA, Pothineni A, Marcus CZ, Bisognano JD. The role of obesity and obstructive sleep apnea in the pathogenesis and treatment of resistant hypertension. Curr Hypertens Rep. 2014;16(1):411. 6. Montesi SB, Edwards BA, Malhotra A, Bakker JP. The effect of continuous positive airway pressure treatment on blood pressure: a systematic review and meta-analysis of randomized controlled trials. J Clin Sleep Med. 2012;8(5):587-596. 7. Andren A, Hedberg P, Walker-Engstrom ML, Wahlen P, Tegelberg A. Effects of treatment with oral appliance on 24-h blood pressure in patients with obstructive sleep apnea and hypertension: a randomized clinical trial. Sleep Breath. 2013;17(2):705-712. 8. Iftikhar IH, Hays ER, Iverson MA, Magalang UJ, Maas AK. Effect of oral appliances on blood pressure in obstructive sleep apnea: a systematic review and meta-analysis. J Clin Sleep Med. 2013;9(2):165-174. 9. White DP, Shafazand S. Mandibular advancement device vs. CPAP in the treatment of obstructive sleep apnea: are they equally

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effective in short term health outcomes? J Clin Sleep Med. 2013;9(9):971-972. 10. Martínez-Garcia MA, Capote F, Campos-Rodríguez F, et al; for the Spanish Sleep Network. Effect of CPAP on blood pressure in patients with obstructive sleep apnea and resistant hypertension: the HIPARCO randomized clinical trial. JAMA. 2013;310(22):2407-2415. 11. Pedrosa RP, Drager LF, de Paula LK, Amaro AC, Bortolotto LA, Lorenzi-Filho G. Effects of OSA treatment on BP in patients with resistant hypertension: a randomized trial. Chest. 2013;144(5):1487-1494. 12. Sanchez-de-la-Torre M, Campos-Rodriguez F, Barbe F. Obstructive sleep apnoea and cardiovascular disease. Lancet Respir Med. 2013;1(1):61-72. 13. Hodgkinson J, Mant J, Martin U, et al. Relative effectiveness of clinic and home blood pressure monitoring compared with ambulatory blood pressure monitoring in diagnosis of hypertension: systematic review. BMJ. 2011;342:d3621. 14. Powers BJ, Olsen MK, Smith VA, Woolson RF, Bosworth HB, Oddone EZ. Measuring blood pressure for decision making and quality reporting: where and how many measures? Ann Intern Med. 2011;154(12):781-788. W-289-W-790. 15. Dernaika TA, Kinasewitz GT, Tawk MM. Effects of nocturnal continuous positive airway pressure therapy in patients with resistant hypertension and obstructive sleep apnea. J Clin Sleep Med. 2009;5(2):103-107. 16. Logan AG, Tkacova R, Perlikowski SM, et al. Refractory hypertension and sleep apnoea: effect of CPAP on blood pressure and baroreflex. Eur Respir J. 2003;21(2):241-247. 17. Lozano L, Tovar JL, Sampol G, et al. Continuous positive airway pressure treatment in sleep apnea patients with resistant hypertension: a randomized, controlled trial. J Hypertens. 2010;28(10): 2161-2168. 18. Martinez-Garcia MA, Gomez-Aldaravi R, Soler-Cataluna JJ, Martinez TG, Bernacer-Alpera B, Roman-Sanchez P. Positive effect of CPAP treatment on the control of difficult-to-treat hypertension. Eur Respir J. 2007;29(5):951-957. 19. Xie X, Pan L, Ren D, Du C, Guo Y. Effects of continuous positive airway pressure therapy on systemic inflammation in obstructive sleep apnea: a meta-analysis. Sleep Med. 2013;14(11): 1139-1150. 20. Xu T, Li T, Wei D, et al. Effect of automatic versus fixed continuous positive airway pressure for the treatment of obstructive sleep apnea: an up-to-date meta-analysis. Sleep Breath. 2012;16(4):1017-1026. 21. Ip S, D’Ambrosio C, Patel K, et al. Auto-titrating versus fixed continuous positive airway pressure for the treatment of obstructive sleep apnea: a systematic review with meta-analyses. Syst Rev. 2012;1:20. 22. Smith I, Lasserson TJ. Pressure modification for improving usage of continuous positive airway pressure machines in adults with obstructive sleep apnoea. Cochrane Database Syst Rev. 2009;4:CD003531. 23. Abdel-Kader K, Dohar S, Shah N, et al. Resistant hypertension and obstructive sleep apnea in the setting of kidney disease. J Hypertens. 2012;30(5):960-966.

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Resistant hypertension in obstructive sleep apnea: is continuous positive airway pressure the next step?

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