Resistant Hypertension in Obstructive Sleep Apnea: Is Continuous Positive Airway Pressure the Next Step?

Abstract

Commentary on 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. Commentary on 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. Resistant 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 mortality1Smith S.M. Gong Y. Handberg E. et al.Predictors and outcomes of resistant hypertension among patients with coronary artery disease and hypertension.J Hypertens. 2014; 32: 635-643Crossref PubMed Scopus (64) Google Scholar and for increased risk of end-stage renal disease.2Tanner R.M. Calhoun D.A. Bell E.K. 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: 781-788Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar 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.3Pedrosa R.P. Drager L.F. Gonzaga C.C. et al.Obstructive sleep apnea: the most common secondary cause of hypertension associated with resistant hypertension.Hypertension. 2011; 58: 811-817Crossref PubMed Scopus (452) Google Scholar, 4Goncalves S.C. Martinez D. Gus M. et al.Obstructive sleep apnea and resistant hypertension: a case-control study.Chest. 2007; 132: 1858-1862Crossref PubMed Scopus (197) Google Scholar 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.5Marcus J.A. Pothineni A. Marcus C.Z. Bisognano J.D. The role of obesity and obstructive sleep apnea in the pathogenesis and treatment of resistant hypertension.Curr Hypertens Rep. 2014; 16: 411Crossref PubMed Scopus (45) Google Scholar 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.6Montesi S.B. Edwards B.A. Malhotra A. Bakker J.P. 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: 587-596PubMed Google Scholar 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.7Andren A. Hedberg P. Walker-Engstrom M.L. 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: 705-712Crossref PubMed Scopus (57) Google Scholar, 8Iftikhar I.H. Hays E.R. Iverson M.A. Magalang U.J. Maas A.K. Effect of oral appliances on blood pressure in obstructive sleep apnea: a systematic review and meta-analysis.J Clin Sleep Med. 2013; 9: 165-174PubMed Google Scholar, 9White D.P. Shafazand S. Mandibular advancement device vs. CPAP in the treatment of obstructive sleep apnea: are they equally effective in short term health outcomes?.J Clin Sleep Med. 2013; 9: 971-972PubMed Google Scholar 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. A recent publication by Martínez-Garcia et al10Martínez-Garcia M.A. Capote F. Campos-Rodríguez F. et al.for the Spanish Sleep NetworkEffect of CPAP on blood pressure in patients with obstructive sleep apnea and resistant hypertension: the HIPARCO randomized clinical trial.JAMA. 2013; 310: 2407-2415Crossref PubMed Scopus (437) Google Scholar 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 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 = 98) or no therapy (n = 96) and followed up for 12 weeks. At baseline, mean AHI was 40.4 ± 18.9 and 24-hour mean BP was 103.4 ± 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 = 0.02) and 24-hour diastolic BP (3.2 mm Hg; 95% CI, 1.0-5.4; P = 0.005), but there was only a trend for improvement in 24-hour systolic BP (3.1 mm Hg; 95% CI, −0.6 to 6.7; P = 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 = 0.02). There also was a significant positive correlation between hours of CPAP use and decrease in 24-hour mean BP (r = 0.29; P = 0.006), systolic BP (r = 0.25; P = 0.02), and diastolic BP (r = 0.30; P = 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 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 al11Pedrosa R.P. Drager L.F. de Paula L.K. Amaro A.C. Bortolotto L.A. Lorenzi-Filho G. Effects of OSA treatment on BP in patients with resistant hypertension: a randomized trial.Chest. 2013; 144: 1487-1494Crossref PubMed Scopus (147) Google Scholar 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.12Sanchez-de-la-Torre M. Campos-Rodriguez F. Barbe F. Obstructive sleep apnoea and cardiovascular disease.Lancet Respir Med. 2013; 1: 61-72Abstract Full Text Full Text PDF PubMed Scopus (292) Google Scholar 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.13Hodgkinson 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: d3621Crossref PubMed Scopus (273) Google Scholar, 14Powers B.J. Olsen M.K. Smith V.A. Woolson R.F. Bosworth H.B. Oddone E.Z. Measuring blood pressure for decision making and quality reporting: where and how many measures?.Ann Intern Med. 2011; 154 (W-289-W-790): 781-788Crossref PubMed Scopus (144) Google Scholar 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. 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 studies15Dernaika T.A. Kinasewitz G.T. Tawk M.M. Effects of nocturnal continuous positive airway pressure therapy in patients with resistant hypertension and obstructive sleep apnea.J Clin Sleep Med. 2009; 5: 103-107PubMed Google Scholar and prospective trials11Pedrosa R.P. Drager L.F. de Paula L.K. Amaro A.C. Bortolotto L.A. Lorenzi-Filho G. Effects of OSA treatment on BP in patients with resistant hypertension: a randomized trial.Chest. 2013; 144: 1487-1494Crossref PubMed Scopus (147) Google Scholar, 16Logan A.G. Tkacova R. Perlikowski S.M. et al.Refractory hypertension and sleep apnoea: effect of CPAP on blood pressure and baroreflex.Eur Respir J. 2003; 21: 241-247Crossref PubMed Scopus (278) Google Scholar, 17Lozano L. Tovar J.L. Sampol G. et al.Continuous positive airway pressure treatment in sleep apnea patients with resistant hypertension: a randomized, controlled trial.J Hypertens. 2010; 28: 2161-2168Crossref PubMed Scopus (207) Google Scholar, 18Martinez-Garcia M.A. Gomez-Aldaravi R. Soler-Cataluna J.J. Martinez T.G. Bernacer-Alpera B. Roman-Sanchez P. Positive effect of CPAP treatment on the control of difficult-to-treat hypertension.Eur Respir J. 2007; 29: 951-957Crossref PubMed Scopus (91) Google Scholar 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,11Pedrosa R.P. Drager L.F. de Paula L.K. Amaro A.C. Bortolotto L.A. Lorenzi-Filho G. Effects of OSA treatment on BP in patients with resistant hypertension: a randomized trial.Chest. 2013; 144: 1487-1494Crossref PubMed Scopus (147) Google Scholar 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.11Pedrosa R.P. Drager L.F. de Paula L.K. Amaro A.C. Bortolotto L.A. Lorenzi-Filho G. Effects of OSA treatment on BP in patients with resistant hypertension: a randomized trial.Chest. 2013; 144: 1487-1494Crossref PubMed Scopus (147) Google Scholar In a post hoc analysis of another prospective trial by Lozano et al,17Lozano L. Tovar J.L. Sampol G. et al.Continuous positive airway pressure treatment in sleep apnea patients with resistant hypertension: a randomized, controlled trial.J Hypertens. 2010; 28: 2161-2168Crossref PubMed Scopus (207) Google Scholar 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 (−4.9 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 al11Pedrosa R.P. Drager L.F. de Paula L.K. Amaro A.C. Bortolotto L.A. Lorenzi-Filho G. Effects of OSA treatment on BP in patients with resistant hypertension: a randomized trial.Chest. 2013; 144: 1487-1494Crossref PubMed Scopus (147) Google Scholar and Lozanao et al17Lozano L. Tovar J.L. Sampol G. et al.Continuous positive airway pressure treatment in sleep apnea patients with resistant hypertension: a randomized, controlled trial.J Hypertens. 2010; 28: 2161-2168Crossref PubMed Scopus (207) Google Scholar used ABPM to identify nocturnal 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.12Sanchez-de-la-Torre M. Campos-Rodriguez F. Barbe F. Obstructive sleep apnoea and cardiovascular disease.Lancet Respir Med. 2013; 1: 61-72Abstract Full Text Full Text PDF PubMed Scopus (292) Google Scholar 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 6.19Xie 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: 1139-1150Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar Future studies investigating the associations between proinflammatory cytokines, resistant hypertension, and effective treatment of OSA are needed to delineate underlying mechanistic pathways. 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,20Xu 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: 1017-1026Crossref PubMed Scopus (30) Google Scholar although other comprehensive meta-analyses have questioned the clinical significance of such findings.21Ip 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: 20Crossref PubMed Scopus (85) Google Scholar, 22Smith I. Lasserson T.J. Pressure modification for improving usage of continuous positive airway pressure machines in adults with obstructive sleep apnoea.Cochrane Database Syst Rev. 2009; 4: CD003531PubMed Google Scholar 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.23Abdel-Kader K. Dohar S. Shah N. et al.Resistant hypertension and obstructive sleep apnea in the setting of kidney disease.J Hypertens. 2012; 30: 960-966Crossref PubMed Scopus (42) Google Scholar 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. 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.