Eur opean Rev iew for Med ical and Pharmacol ogical Sci ences 2016; 20: 339-344 Effect of bedtime dosing of barnidipine hydrochloride in non-dipper hypertensive patients with obstructive sleep apnoea not treated with continuous positive airway pressure

G. CRIPPA, D. ZABZUNI, A. CASSI, E. BRAVI

Department of Internal Medicine, Hypertension Unit, Guglielmo Da Saliceto Hospital, Piacenza, Italy

Abstract. – OBJECTIVE: Obstructive sleep ap - Abbreviations noea (OSA) is considered a cause of secondary hypertension. About 50% of patients with OSA show elevated blood pressure levels. Non-dipper OSA = obstructive sleep apnoea; CPAP = continuous pattern (blunted or absent nocturnal decrease of positive airway pressure; ABP = Ambulatory blood pres - blood pressure) is frequently observed in patients sure ; CCB = calcium channel blocker . with OSA and is associated with increased cere - bral, cardiovascular and renal events. The aim of this study was to observe the effect of barnidipine calcium channel blocker on these patients. Introduction PATIENTS AND METHODS: Forty-one pa - tients (mean age 69 ± 17 years, 18 females) with Obstructive sleep apnoea ( OSA) syndrome is a previously diagnosed OSA (by reduced channel common condition affecting around 5% of the gen - home-based polysomnography) who were not eral population. It is consistently more prevalent in being treated with continuous positive airway 1-2 pressure (CPAP) because of contraindications males with a male to female ratio of up to 8:1 . or because of patient intolerance or rejection The association between OSA and hyperten - were evaluated. Non-dipper status was defined sion is well documented. Scientific data and clin - as the presence of a nighttime fall in systolic ical awareness regarding the interaction between blood pressure (BP) which was < 10% that of OSA and hypertension are continuously increas - daytime systolic BP as observed in a previous ing 3. Approximately 50% of patients with OSA ambulatory blood pressure (ABP) monitoring. OSA was defined according to the presence of are hypertensive, and an estimated 40% of hyper - 4-6 5 or more episodes per hour of apnoea, hypop - tensive patients have OSA . noea or arousal due to respiratory effort. The prevalence of hypertension in OSA syn - The reproducibility of non-dipping status was drome appears to be influenced by the severity of confirmed through a second 24-h ABP monitor - the breathing disorder. In patients with OSA an ing performed at baseline. On top of the previ - ous stable treatment regimen (which excluded augmented sympathetic activity at rest, which per - calcium-channel blockers), a 10 mg dosing of sists not only during the apneas, has been ob - barnidipine hydrochloride at bedtime was added served . The increased sympathetic tone affects to all subjects during a 12-week period. vascular resistance, cardiac output, and renin-an - RESULTS: Among the 41 non-dipper patients, giotensin-aldosterone system activity. These 32 (78%) showed complete normalization of cir - changes play an essential role in the genesis of the cadian rhythm. Add-on treatment with barnidip - ine was generally well tolerated. organism’s acute and chronic responses, and part - CONCLUSIONS: Bedtime dosing of the calci - ly explain the pathophysiological mechanisms be - um-channel blocker (CCB) barnidipine signifi - hind the chronic cardiovascular consequences re - cantly reduced mean nighttime systolic and di - lated to OSAS, and in particular hypertension 7-11 . astolic ABP in hypertensive patients presenting One of the characteristics of hypertensive pa - with non-dipper pattern and OSA – not on CPAP tients with OSA is the blunted nocturnal decline treatment. Moreover, it restored the previously 3,12-14 altered circadian rhythm in the majority of them. in blood pressure (non-dipper pattern) . The specific relationship between non-dipper status Key Words: and the risk of cerebral, cardiovascular and renal Barnidipine hydrochloride, Non-dipper pattern, events is well established 15-18 . Therefore, the nor - Obstructive sleep apnoea, ABP monitoring. malization of the circadian BP rhythm should be

Corresponding Author: Dorjan Zabzuni, MD; e-mail: [email protected] 339 G. Crippa, D. Zabzuni, A. Cassi, E. Bravi considered an important goal of antihypertensive The aim of our study was to evaluate the effect treatment. of an add-on bedtime dosing of barnidipine on A better lifestyle and dietary intervention the circadian rhythm of BP in non-dipper hyper - should always be considered as the first step in tensive patients with OSA, who were not being the treatment of patients with OSA. treated with CPAP because of contraindications Overweight/obesity and a sedentary lifestyle or patient intolerance or rejection . are very common in such patients , as well as al - Barnidipine hydrochloride is a safe, effective cohol and tobacco consumption. Thus, body and well tolerated dihydropyridine calcium chan - weight reduction, increased physical activity, nel blocker, available in a modified-release for - smoking cessation and alcohol intake reduction mulation, which has a gradual onset of action should be suggested to all apnoeic subjects, inde - and a sustained effect. Its antihypertensive action pendently of the presence of hypertension or oth - is mainly related to the reduction of peripheral er cardiovascular risk factors. vascular resistance 33 -36 . Other measures such as avoiding the supine position (lying on one’s back) during sleep in the event of positional OSA, the use of mandibular Patients and Methods advancement prosthesis (oral appliance) or, more rarely, surgery, have shown some positive effects In a post-hoc analysis of a larger observational in the management of OSA syndrome. However, study 37-38 , in which we evaluated the response to in terms of specific therapies, continuous posi - the add-on treatment with barnidipine in non-dip - tive airway pressure (CPAP) remains the refer - per hypertensive patients, we have analyzed the ence treatment for OSA. effect of this calcium-channel blocker in a subset Prospective cohort studies in patients with of patients with OSA. We considered 41 pharma - OSA syndrome have shown that treatment with cologically treated non-dipper hypertensive pa - CPAP significantly reduces the risk of cardiovas - tients (18 females, mean age 69 ± 17 years) with cular events in patients with severe OSA 19-22 . OSA and who were not being treated with CPAP. The effects of CPAP on BP have also been in - The evaluation of respiratory disorder was car - vestigated , but the results of these studies are ried out by using a reduced channel home-based sometimes divergent and not conclusive. Some device (Embletta X 100, Broomfield, CO, USA). studies show a beneficial effect with significant Overnight Polysmnography was evaluated by an systolic and diastolic BP reduction , while others experienced pulmonologist. show only a minor and non-significant reduction OSA was defined as the detection of 5 or more in BP 23-29 . symptomatic events per hour ( apnoea , hypop - Only a few studies have analyzed the varia - noea or arousal due to breathing effort) or 15 or tions in dipper/non-dipper profiles with CPAP more events per hour in the absence of reported treatment and their results are not homoge - symptoms. Patients with a central apnoea index neous 24-27 . above 5 were excluded. One of the concerns regarding CPAP treat - Non-dipper pattern was defined as the pres - ment is adherence to the therapy. When adher - ence of a nighttime fall in ambulatory systolic ence is defined as the use of CPAP for more than blood pressure which constituted less than 10 % 4 hours per night, 46 to 83% of apnoeic patients of daytime systolic blood pressure at baseline. have been reported as being non-adherent to Patients with symptomatic hypotension during treatment 30 ,31 . Furthermore, it is a common clini - the entire ABPM recording were excluded. cal observation that the proposal of CPAP treat - ABP monitoring was performed by using a non- ment is often rejected by many patients. invasive, portable validated recorder (SpaceLabs Regarding antihypertensive therapy , there is Inc. model 90207-30). Patients wore the device for no obvious antihypertensive drug class that has 24 hours on all days except holidays and the repeatedly demonstrated superior efficacy in recorder was set to take readings every 15 minutes OSA patients with hypertension 32 . during daytime (7 am to 11 pm) and every 30 min - However, the altered circadian rhythm that utes during nighttime (11 pm to 7 am) . may characterise apnoeic hypertensive individu - The analysis of ABP monitorings, the evalua - als, suggests that, the increased antihypertensive tion of daytime nighttime and circadian rhythm efficacy during nighttime could, at least theoreti - and the night-to-day BP ratio were performed ac - cally, reverse the non-dipper pattern. cording to the 2013 ESH-ESC guidelines 39 .

340 Barnidipine bedtime administration in non-dipper hypertensive patients with OSA

ABP recording was considered complete when Results 80% or more of the scheduled readings were available , with at least 2 valid readings per hour. The study was completed in forty-one individ - Antihypertensive treatment included an - uals 41 with moderate-to-severe OSA , as well as giotensin-converting-enzyme inhibitors, early- hypertension with confirmed non-dipper pattern. distal-tubule diuretics, angiotensin-receptor All patients had mean daytime ABP values blockers and beta-adrenergic blockers , while pa - above 135/85 mmHg and mean nighttime ABP tients being treated with calcium-channel block - values above 120/70 mmHg. In all patients , the ers of any kind were excluded from the study. nocturnal systolic mean ABP fall resulted in less Before enrollment, all patients had been receiv - than 10% with respect to daytime mean values ing stable antihypertensive treatment during the (night-day BP ratio > 0.9). previous 2 months at least, without changes in Among the 41 patients, 9 of them showed a dosage or type of drug. riser pattern, with BP increasing rather than dip - All patients received a 10 mg dosing of barni - ping during the night. dipine hydrochloride, to be taken at bedtime (10- At baseline , diurnal and nocturnal ABP aver - 11 pm), in addition to their previous treatment aged 139.1 ± 9.6/87.4 ± 7.7 and 135.8 ± 9.9 /85.1 regimen. ± 8.1 mmHg, respectively. A 24-hour ABP monitoring was repeated after After an add-on treatment with barnidipine at 12 weeks of treatment . bedtime, a BP decrease was observed in both pe - The Ethical Committee approved the study, riods. and all participants gave their informed written The mean ABP was 129.8 ± 8.9/82.1 ± 7.1 consent . mmHg for daytime and 118.2 ± 7.9/ 76.6± 6.9 mmHg for nighttime after the second 24-hour Statistical Analysis monitoring. Diurnal and nocturnal, systolic and The primary outcome variable was the change diastolic differences reached statistical signifi - in nighttime mean systolic and diastolic ABP. cance ( p<0.05 for daytime mean systolic and di - The secondary outcome variable was the normal - astolic values and p< 0.025 for nighttime mean ization of the non-dipper pattern. systolic and diastolic values). Statistical software (SPSS version 18.0 for The main results are depicted in the Table I . Windows; Chicago, IL, USA) was used for data The mean differences between daytime and processing and statistical analysis. Continuous nighttime BP were 3.3 ± 5.6/2.3 ± 4.9 mmHg at variables are expressed as a mean ± SD, and qual - baseline . The corresponding differences at the itative variables are expressed as a percentage. second ABPM after the add-on treatment were Changes in ABP systolic and diastolic values 11.6 ± 10.6/5.5 ± 7.1 mmHg for systolic and di - (mean 24-h BP, daytime BP and nighttime BP) astolic ABP respectively ( p<0.05) . after intervention were compared to baseline val - Among the 41 non-dipper patients , 32 (78%) ues by using the Student’s t-test for paired sam - showed complete normalization of circadian ples (two-sided, alpha level p<0.05). To compare rhythm ( p<0.05). two qualitative variables with repeated measures, The hourly mean ABP before and after inter - the non-parametric test of Wilcoxon for paired vention are depicted in the Figure 1. samples was used. The circadian pattern after barnidipine bed- The sample size was calculated to detect a time add-on treatment was clearly and signifi - change of 4 mm Hg in nighttime systolic ABP cantly modified with a more pronounced shift compared to baseline. during nighttime (11 pm-7 am).

Table I. Average ambulatory blood pressure (ABP) values before and after bedtime administration of barnidipine 10 mg. The data are expressed as mean values ± SD. Student’s t-test for paired samples (two-sided, alpha level p < 0.05).

Before barnidipine dosing After barnidipine dosing p

Daytime Systolic ABP 139.1 ± 9.6 129.8 ± 8.9 <0.05 Daytime Diastolic ABP 87.4 ± 7.7 82.1 ± 7.1 <0.05 Nighttime Systolic ABP 135.8 ± 9.9 118.2 ± 7.9 <0.025 Nighttime Diastolic ABP 85.1 ± 8.1 76.6 ± 6.9 <0.025

341 G. Crippa, D. Zabzuni, A. Cassi, E. Bravi

Figure 1. Hourly mean ABP obtained before and after bedtime administration of barnidipine 10 mg in 41 patients.

Add-on treatment with barnidipine normalized OSA constitutes a relevant cardiovascular risk the previously altered circadian rhythm in 78% factor, particularly when associated with hyper - of the patients who concluded the study (p<0.05, tension and a non-dipper BP pattern . test of Wilcoxon for paired samples ). CPAP treatment is still performed in a minori - Add-on treatment with barnidipine was gener - ty of patients, and even in those with more seri - ally well tolerated. ous forms of OSA. Three patients developed mild symptomatic The relevant proportion of normalization of diurnal hypotension and 6 showed mild-to- circadian BP rhythm obtained in this particular moderate leg oedema. Both side effects did not group of patients (not treated for OSA and non- require treatment withdrawal . dipper hypertension) seems very promising. In fact, considering the high cardiovascular risk profile of patients with OSA and the well -estab - Discussion lished correlations between nocturnal BP levels and cardiovascular morbidity and mortality, the A bedtime dosing of the calcium-channel reversal of the altered BP circadian rhythm blocker barnidipine (added to a previous , stable should be considered an extremely important antihypertensive treatment) significantly reduced goal. systolic and diastolic ABP in non-dipper hyper - A potential limitation with regards to this tensive patients with OSA syndrome, who were study is the lack of a placebo-control group , not being treated with CPAP, since it was designed to be observational , inter - Bedtime administration of barnidipine 10 mg ventional and prospective . However, the antihy - was more effective on nighttime ABP than on pertensive effect of barnidipine has been proper - daytime ABP. ly demonstrated in randomized, double-blind, Add-on treatment with barnidipine normal - placebo-controlled studies and our results may be iszed the previously altered circadian rhythm in considered complementary to those previous the great majority (78 %) of the patients who studies 34,40 . concluded the study. The choice of carrying out a study with obser - Barnidipine was generally well tolerated and vational design was determined by the particular no patients were withdrawn from the study due characteristics of the participating patients and to adverse events. the strict inclusion criteria (OSA not being treat -

342 Barnidipine bedtime administration in non-dipper hypertensive patients with OSA ed with CPAP, BP values not on target, non-dip - 7) SMITH RP, V EALE D, P ÉPIN JL, L ÉVY PA. Obstructive per/riser ABP patterns, stable treatment exclud - sleep apnoea and the autonomic nervous sys - ing CCB). A randomized, placebo-control design tem. Sleep Med Rev 1998; 2: 69-92. would have greatly limited the number of obser - 8) BAGUET JP, B ARONE -R OCHETTE G, P ÉPIN JL. Hyperten - sion and obstructive sleep apnoea syndrome: vations and increased the expenditures required current perspectives. J Hum Hypertens 2009; 23: to cover insurance. 431-443. 9) CARLSON JT, H EDNER J, E LAM M, E JNELL H, S ELLGREN J, WALLIN BG. Augmented resting sympathetic activi - Conclusions ty in awake patients with obstructive sleep apnea. Chest 1993; 103: 1763-1768. The bedtime dosing of barnidipine, in hyper - 10) SOMERS VK, D YKEN ME, C LARY MP, A BBOUD FM. Sym - tensive patients with non-dipper pattern and pathetic neural mechanisms in obstructive sleep apnea. J Clin Invest 1995; 96: 1897-1904. OSA, not being treated with CPAP, significantly reduced mean nighttime systolic and diastolic 11) GADDAM K, P IMENTA E, T HOMAS SJ, C OFIELD SS, O PARIL S, H ARDING SM, C ALHOUN DA. Spironolactone re - ABP and, in the majority of these patients, re - duces severity of obstructive sleep apnoea in pa - stored the previously altered circadian rhythm. tients with resistant hypertension: a preliminary These findings may be of particular interest report. J Hum Hypertens 2010; 24: 532-537. since CPAP treatment is not feasible for many 12) HLA KM, Y OUNG T, F INN L, P EPPARD PE, S ZKLO -C OXE hypertensive patients with a non-dipper pattern M, S TUBBS M. Longitudinal association of sleep- associated with OSA . disordered breathing and non-dipping of noctur - nal blood pressure in the Wisconsin Sleep cohort Study. Sleep 2008; 31: 795-800. 13) BAGUET JP, H AMMER L, L EVY P, P IERRE H, R OSSINI E, –––––––––––––––– –-– –– MOURET S, O RMEZZANO O, M ALLION JM, P ÉPIN JL. Conflict of Interest Night-time and diastolic hypertension are com - The Authors declare that they have no conflict of interests. mon and underestimated conditions in newly di - agnosed apnoeic patients. J Hypertens 2005; 23: 521-527. 14) WOLF J, H ERING D, N ARKIEWICZ K. Nondipping pat - References tern of hypertension and obstructive sleep apnea syndrome. Hypertens Res 2010; 33: 867-871. 1) YOUNG T, P EPPARD PE, G OTTLIEB DJ. Epidemiology of obstructive sleep apnea: a population health per - 15) OHKUBO T, H OZAWA A, Y AMAGUCHI J, K IKUYA M, OHMORI K, M ICHIMATA M, M ATSUBARA M, H ASHIMOTO J, spective. Am J Respir Crit Care Med 2002; 165: HOSHI H, A RAKI T, T SUJI I, S ATOH H, H ISAMICHI S, I MAI Y. 1217-1239. Prognostic significance of the nocturnal decline in 2) PERLIS ML, L ICHSTEIN KL. Treating Sleep Disorders: blood pressure in individuals with and without Principles and Practice of Behavioral Sleep Medi - high 24-h blood pressure: the Ohasama study. J cine. John Wiley & Sons, 2003; pp .77-100. Hypertens 2002; 20: 2183-2189. 3) PARATI G, L OMBARDI C, H EDNER J, B ONSIGNORE MR, 16) BEN -D OV IZ, K ARK JD, B EN -I SHAY D, M EKLER J, B EN - GROTE L, T KACOVA R, L EVY P, R IHA R, B ASSETTI C, ARIE L, B URSZTYN M. Predictors of all-cause mortali - NARKIEWICZ K, M ANCIA , M CNICHOLAS WT. on behalf ty in clinical ambulatory monitoring: unique as - of the EU COST ACTION B26 members. Posi - pects of blood pressure during sleep. Hyperten - tion paper on the management of patients with sion 2007; 49: 1235-1241. obstructive sleep apnea and hypertension: joint 17) DOLAN E, S TANTON A, T HIJS L, H INEDI K, A TKINS N, M C- recommendations by the European Society of CLORY S, D EN HOND E, M CCORMACK P, S TAESSEN JA, Hypertension, by the European Respiratory So - O’B RIEN E. Superiority of ambulatory over clinic ciety and by the members of European COST blood pressure measurement in predicting mor - (Co-operation in Scientific and Technological re - tality: the Dublin outcome study. Hypertension search) ACTION B26 on obstructive sleep ap - 2005; 46: 156-161. nea. J Hypertens 2012; 30: 633-646. 18) VERDECCHIA P, P ORCELLATI C, S CHILLACI G, B ORGIONI C, 4) LAVIE P, B EN -Y OSEF R, R UBIN AE. Prevalence of sleep CIUCCI A, B ATTISTELLI M, G UERRIERI M, G ATTESCHI C, apnea syndrome among patients with resistant ZAMPI I, S ANTUCCI A, S ANTUCCI C, R EBOLDI G. Ambula - hypertension. Am Heart J 1984; 108: 373-376. tory blood pressure: an independent predictor of 5) WORSNOP CJ, N AUGHTON MT, B ARTER CE, M ORGAN prognosis in essential hypertension. Hyperten - TO, A NDERSON AI, P IERCE RJ. The prevalence of ob - sion 1994; 24: 793-801. structive sleep apnea in hypertensives. Am J Crit 19) MARIN JM, C ARRIZO SJ, V ICENTE E, A GUSTI AG . Care Med 1998; 157: 111-115. Longterm cardiovascular outcomes in men with 6) CALHOUN DA. Obstructive sleep apnea and hyper - obstructive sleep apnoea-hypopnoea with or with - tension. Curr Hypertens Rep 2010; 12: 189-195. out treatment with continuous positive airway

343 G. Crippa, D. Zabzuni, A. Cassi, E. Bravi

pressure: an observational study. Lancet 2005; 30) WEAVER TE, G RUNSTEIN RR. Adherence to Continu - 365: 1046-1053. ous Positive Airway Pressure Therapy. Proc Am 20) CAMPOS -R ODRIGUEZ F, P EÑA -G RIÑAN N, R EYES -N UÑEZ N, Thorac Soc 2008; 5: 173-178. DE LA CRUZ -M ORON I, P EREZ -R ONCHEL J, D E LA VEGA - 31) SAWYER AM, G OONERATNE NS, M ARCUS CL, O FER D, GALLARDO F, F ERNANDEZ -P ALACIN A. Mortality in ob - RICHARDS KC, W EAVER TE. A systematic review of structive sleep apnea-hypopnea patients treated CPAP adherence across age groups: clinical and with positive airway pressure. Chest 2005; 128: empiric insights for developing CPAP adherence 624-633. interventions. Sleep Med Rev 2011; 15: 343-356. 21) DOHERTY LS, K IELY JL, S WAN V, M CNICHOLAS WT . 32) ZIEGLER MG, M ILIC M, S UN P. Antihypertensive ther - Long-term effects of nasal continuous positive apy for patients with obstructive sleep apnea. airway pressure therapy on cardiovascular out - Curr Opin Nephrol Hypertens 2011; 20: 50-55. comes in sleep apnea syndrome. Chest 2005; 33) TERAMURA T, W ATANABE T, H IGUCHI S, H ASHIMOTO K. 127: 2076-2084. Pharmacokinetics of barnidipine hydrochloride, a 22) YAGGI HK, C ONCATO J, K ERNAN WN, L ICHTMAN JH, new dihydropyridine calcium channel blocker, in BRASS LM, M OHSENIN V. Obstructive sleep apnea as the rat, dog and human. Xenobiotica 1995; 25: a risk factor for stroke and death. N Engl JMed. 1237-1246. 2005; 353: 2034-2041. 34) MALHOTRA HS, P LOSKER GL. Barnidipine. Drugs 23) BAZZANO LA, K HAN Z, R EYNOLDS K, H E J. Effect of 2001; 61: 989-996. nocturnal nasal continuous positive airway pres - 35) LIAU CS. Barnidipine: A new calcium channel sure on blood pressure in obstructive sleep ap - blocker for hypertension treatment. Expert Rev nea. Hypertension 2007; 50: 417-423. Cardiovasc Ther 2005; 3: 207-213. 24) DIMSDALE JE, L OREDO JS, P ROFANT J. Effect of contin - 36) SPIROU A, R IZOS E, L IBEROPOULOS EN, K OLAITIS N, A CHI - uous positive airway pressure on blood pressure: MASTOS A, T SELEPIS AD, E LISAF M. Effect of barnidip - a placebo trial. Hypertension 2000; 35: 144-147. ine on blood pressure and serum metabolic para - 25) PEPPERELL JCT, R AMDASSINGH -D OW S, C ROSTHWAITE N, meters in patients with essential hypertension: a MULLINS R, J ENKINSON C, S TRADLING JR, D AVIES RJ. pilot study. J Cardiovasc Pharmacol Ther 2006; Ambulatory blood pressure after therapeutic and 11: 256-261. subtherapeutic nasal continuous positive airway 37) CRIPPA G, C ASSI A, B RAVI E, F ARES ML, C AVALLOTTI P. The pressure for obstructive sleep apnea: a random - bedtime dosing of barnidipine hydrochloride re - ized parallel trial. Lancet 2002; 359: 204-210. stores circadian rhythm in nondipper hypertensive 26) BECKER HF, J ERRENTRUP A, P LOCH T, G ROTE L, P ENZEL T, patients. J Hypertens 2010; 28(A Suppl): e541. SULLIVAN CE, P ETER JH. Effect of nasal continuous 38) CRIPPA G, F ARES ML, C ASSI A, Z ABZUNI D, B RAVI E. Ef - positive airway pressure treatment on blood pres - fect of bedtime dosing of barnidipine hydrochlo - sure in patients with obstructive sleep apnea. Cir - ride in non-dipper hypertensive patients with ob - culation 2003; 107: 68-73. structive sleep apnoea not treated with continu - 27) CAMPOS -R ODRIGUEZ F, G RILO -R EINA A, P EREZ -R ONCHEL J, ous positive airway pressure. J Clin Hypertens MERINO -S ANCHEZ M, G ONZALEZ -B ENITEZ MA, B ELTRAN - 2013; 15(1 Suppl): 7S. ROBLES M, A LMEIDA -G ONZALEZ C. Effect of continu - 39) MANCIA G, F AGARD R, N ARKIEWICZ K, R EDÓN J, ous positive airway pressure on ambulatory BP in ZANCHETTI A, B ÖHM M, C HRISTIAENS T, C IFKOVA R, D E patients with sleep apnea and hypertension: a BACKER G, D OMINICZAK A, G ALDERISI M, G ROBBEE DE, placebo-controlled trial. Chest 2006; 129: 1459- JAARSMA T, K IRCHHOF P, K JELDSEN SE, L AURENT S, 1467. MANOLIS AJ, N ILSSON PM, R UILOPE LM, S CHMIEDER RE, 28) ROBINSON GV, S MITH DM, L ANGFORD BA, D AVIES RJ, ANTON SIRNES P, S LEIGHT P, V IIGIMAA M, W AEBER B, STRADLING JR. Continuous positive airway pressure ZANNAD F. 2013 ESH/ESC Guidelines for the does not reduce blood pressure in nonsleepy hy - management of arterial hypertension: the Task pertensive OSA patients. Eur Respir J 2006; 27: Force for the management of arterial hyperten - 1229-1235. sion of the European Society of Hypertension 29) BARBE F, M AYORALAS LR, D URAN J, M ASA JF, M AIMÓ A, (ESH) and of the European Society of Cardiology MONTSERRAT JM, M ONASTERIO C, B OSCH M, L ADARIA A, (ESC). J Hypertens 2013; 31: 1281-357. RUBIO M, R UBIO R, M EDINAS M, H ERNANDEZ L, V IDAL 40) IMAI Y, A BE K, N ISHIYAMA A, S EKINO M, Y OSHINAGA K. S, D OUGLAS NJ, A GUSTÍ AG. Treatment with continu - Evaluation of the antihypertensive effect of barni - ous positive airway pressure is not effective in dipine, a dihydropyridine calcium entry blocker, patients with sleep apnea but no daytime sleepi - as determined by the ambulatory blood pressure ness: a randomized, controlled study. Ann Intern level averaged for 24 h, daytime, and nighttime. Med 2001; 134: 1015-1023. Am J Hypertens 1997; 10: 1415-1419.

344