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.