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      The effect of antihypertensive agents on sleep apnea: protocol for a randomized controlled trial


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          Obstructive sleep apnea (OSA) and hypertension are well-known cardiovascular risk factors. Their control could reduce the burden of heart disease across populations. Several drugs are used to control hypertension, but the only consistently effective treatment of OSA is continuous positive airway pressure. The identification of a drug capable of improving OSA and hypertension simultaneously would provide a novel approach in the treatment of both diseases.


          This is a randomized double-blind clinical trial, comparing the use of chlorthalidone with amiloride versus amlodipine as a first drug option in patients older than 40 years of age with stage I hypertension (140 to 159/90 to 99 mmHg) and moderate OSA (15 to 30 apneas/hour of sleep). The primary outcomes are the variation of the number of apneas per hour and blood pressure measured by ambulatory blood pressure monitoring. The secondary outcomes are adverse events, somnolence scale (Epworth), ventilatory parameters and C reactive protein levels. The follow-up will last 8 weeks. There will be 29 participants per group. The project has been approved by the ethics committee of our institution.


          The role of fluid retention in OSA has been known for several decades. The use of diuretics are well established in treating hypertension but have never been appropriately tested for sleep apnea. As well as testing the efficacy of these drugs, this study will help to understand the mechanisms that link hypertension and sleep apnea and their treatment.

          Trial registration

          ClinicalTrials.gov: NCT01896661

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          Most cited references23

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          2007 Guidelines for the management of arterial hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC).

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            Obstructive sleep apnea syndrome in the Sao Paulo Epidemiologic Sleep Study.

            To estimate the prevalence of Obstructive Sleep Apnea Syndrome (OSAS), using current clinical and epidemiological techniques, among the adult population of Sao Paulo, Brazil. This population-based survey used a probabilistic three-stage cluster sample of Sao Paulo inhabitants to represent the population according to gender, age (20-80 years), and socio-economic status. Face-to-face interviews and in-lab full-night polysomnographies using a nasal cannula were performed. The prevalence of OSAS was determined according to the criteria of the most recent International Classification of Sleep Disorders (ICDS-2) from American Academy of Sleep Medicine (2005). A total of 1042 volunteers underwent polysomnography (refusal rate=5.4%). The mean age+/-SD was 42+/-14 years; 55% were women and 60% had a body mass index>25 kg/m(2). OSAS was observed in 32.8% of the participants (95% CI, 29.6-36.3). A multivariate logistic regression model identified several independent and strong associations for the presence of OSAS: men had greater association than women (OR=4.1; 95% CI, 2.9-5.8; P<0.001) and obese individuals (OR=10.5; 95% CI, 7.1-15.7; P<0.001) than individuals of normal weight. The adjusted association factor increased with age, reaching OR=34.5 (95% CI, 18.5-64.2; P<0.001) for 60-80 year olds when compared to the 20-29 year old group. Low socio-economic status was a protective factor for men (OR=0.4), but was an associated factor for women (OR=2.4). Self-reported menopause explained this increased association (age adjusted OR=2.1; 95% CI, 1.4-3.9; P<0.001), and it was more frequent in the lowest class (43.1%) than either middle class (26.1%) or upper class (27.8%) women. This study is the first apnea survey of a large metropolitan area in South America identifying a higher prevalence of OSAS than found in other epidemiological studies. This can be explained by the use of the probabilistic sampling process achieving a very low polysomnography refusal rate, the use of current techniques and clinical criteria, inclusion of older groups, and the higher prevalence of obesity in the studied population. Copyright 2010 Elsevier B.V. All rights reserved.
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              Cardiovascular protection and blood pressure reduction: a meta-analysis.

              Whether antihypertensive drugs offer cardiovascular protection beyond blood pressure lowering has not been established. We aimed to investigate whether pharmacological properties of antihypertensive drugs or reduction of systolic pressure accounted for cardiovascular outcome in hypertensive or high-risk patients. In a meta-analysis we extracted summary statistics from published reports, and calculated pooled odds ratios for experimental versus reference treatment. We correlated across-trials odd ratios for differences in systolic pressure between groups. We analysed nine randomised trials comparing treatments in 62605 hypertensive patients. Compared with old drugs (diuretics and b-blockers), calcium-channel blockers and angiotensin converting-enzyme inhibitors offered similar overall cardiovascular protection, but calcium-channel blockers provided more reduction in the risk of stroke (13.5%, 95% CI 1.3-24.2, p=0.03) and less reduction in the risk of myocardial infarction (19.2%, 3.5-37.3, p=0.01). Heterogeneity was significant between trials because of high risk of cardiovascular events on doxazosin in one trial, and high risk of stroke on captopril in another; but systolic pressure differed between groups in these two trials by 2-3 mm Hg. Similar systolic differences occurred in a trial of diltiazem versus old drugs, and in three trials of converting-enzyme inhibitor against placebo in high-risk patients. Meta-regression across 27 trials (136124 patients) showed that odds ratios could be explained by achieved differences in systolic pressure. Our findings emphasise that blood pressure control is important. All antihypertensive drugs have similar long-term efficacy and safety. Calcium-channel blockers might be especially effective in stroke prevention. We did not find that converting-enzyme inhibitors or a-blockers affect cardiovascular prognosis beyond their antihypertensive effects.

                Author and article information

                BioMed Central
                2 January 2014
                : 15
                : 1
                [1 ]Postgraduate Studies Program in Cardiology, School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
                [2 ]Division of Cardiology, Hospital de Clinicas de Porto Alegre, Porto Alegre, RS, Brazil
                Copyright © 2014 Cichelero et al.; licensee BioMed Central Ltd.

                This is an open access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Study Protocol


                diuretics, amlodipine, chlorthalidone, hypertension, treatment, sleep apnea


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