title: Chronotherapy for hypertension in obstructive sleep apnoea (CHOSA): a randomised, double-blind, placebo-controlled crossover trial.
abstract: Obstructive sleep apnoea (OSA) is an important cause of secondary hypertension. Nocturnal hypertension is particularly prevalent in OSA and is a strong predictor of cardiovascular mortality. Studies in patients with essential hypertension have suggested that nocturnal administration of antihypertensives improves nocturnal blood pressure (BP) without elevating daytime BP. We evaluated the efficacy of this technique in patients with OSA with stage I/II hypertension, both before and after the addition of CPAP.
  
  
  
  In this double-blind randomised placebo-controlled crossover trial, patients with moderate-to-severe OSA and hypertension received 6 weeks each of evening or morning perindopril with opposing time-matched placebo. CPAP therapy was subsequently added for 8 weeks in addition to either morning or evening perindopril. The primary outcome was sleep systolic BP (SBP) using 24-hour BP monitoring, analysed using linear mixed models.
  
  
  
  Between March 2011 and January 2015, 85 patients were randomised, 79 completed both dosing times, 78 completed the CPAP phase. Sleep SBP reduced significantly from baseline with both evening (-6.9 mm Hg) and morning (-8.0 mm Hg) dosing, but there was no difference between dosing times (difference: 1.1 mm Hg, 95% CI -0.3 to 2.5). However, wake SBP reduced more with morning (-9.8 mm Hg) than evening (-8.0 mm Hg) dosing (difference: 1.8 mm Hg, 95% CI 1.1 to 2.5). Addition of CPAP to either evening or morning dosing further reduced sleep SBP, but by a similar amount (evening: -3.2 mm Hg, 95% CI -5.1 to -1.3; morning: -3.3 mm Hg, 95% CI -5.2 to 1.5).
  
  
  
  Our findings support combining OSA treatment with morning administration of antihypertensives. Unlike in essential hypertension, our results do not support evening administration of antihypertensives, at least with perindopril. Further research is required before this strategy can be widely adopted into hypertension guidelines and clinical practice.
  
  
  
  ACTRN12611000216910, Results.
authors.affiliation: NHMRC Centre for Integrated Research and Understanding of Sleep (CIRUS), and NHMRC Neurosleep Centre Woolcock Institute of Medical Research, The University of Sydney, Sydney, New South Wales, Australia.|Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Yasmina
authors.initials: Y
authors.lastname: Serinel
authors.affiliation: NHMRC Centre for Integrated Research and Understanding of Sleep (CIRUS), and NHMRC Neurosleep Centre Woolcock Institute of Medical Research, The University of Sydney, Sydney, New South Wales, Australia.|Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.|Department of Respiratory and Sleep Medicine, Royal Prince Alfred Hospital, Newtown, New South Wales, Australia.
authors.forename: Brendon J
authors.initials: BJ
authors.lastname: Yee
authors.affiliation: NHMRC Centre for Integrated Research and Understanding of Sleep (CIRUS), and NHMRC Neurosleep Centre Woolcock Institute of Medical Research, The University of Sydney, Sydney, New South Wales, Australia.|Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.|Department of Respiratory and Sleep Medicine, Royal Prince Alfred Hospital, Newtown, New South Wales, Australia.
authors.forename: Ronald R
authors.initials: RR
authors.lastname: Grunstein
authors.affiliation: NHMRC Centre for Integrated Research and Understanding of Sleep (CIRUS), and NHMRC Neurosleep Centre Woolcock Institute of Medical Research, The University of Sydney, Sydney, New South Wales, Australia.|Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.|Department of Respiratory and Sleep Medicine, Royal Prince Alfred Hospital, Newtown, New South Wales, Australia.
authors.forename: Keith H
authors.initials: KH
authors.lastname: Wong
authors.affiliation: Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.|Department of Respiratory and Sleep Medicine, Royal North Shore Hospital, Sydney, New South Wales, Australia.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Cistulli
authors.affiliation: The George Institute for Global Health, Sydney, New South Wales, Australia.|Department of Preventive Medicine and Public Health, Faculty of Medicine, Fukuoka University, Fukuoka, Japan.
authors.forename: Hisatomi
authors.initials: H
authors.lastname: Arima
authors.affiliation: NHMRC Centre for Integrated Research and Understanding of Sleep (CIRUS), and NHMRC Neurosleep Centre Woolcock Institute of Medical Research, The University of Sydney, Sydney, New South Wales, Australia.|Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.|Department of Respiratory and Sleep Medicine, Royal North Shore Hospital, Sydney, New South Wales, Australia.
authors.forename: Craig L
authors.initials: CL
authors.lastname: Phillips
mesh_terms: D000328:Adult; D000368:Aged; D000959:Antihypertensive Agents / Q000008:administration & dosage*; D001794:Blood Pressure / Q000187:drug effects; D018660:Blood Pressure Monitoring, Ambulatory / Q000379:methods; D045422:Continuous Positive Airway Pressure / Q000379:methods; D018592:Cross-Over Studies; D004311:Double-Blind Method; D055870:Drug Chronotherapy; D005260:Female; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D020913:Perindopril / Q000008:administration & dosage*; D020181:Sleep Apnea, Obstructive / Q000150:complications* / Q000503:physiopathology / Q000628:therapy
chemical_list: D000959:Antihypertensive Agents; D020913:Perindopril
keywords: Sleep apnoea