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Chronotherapy for hypertension in obstructive sleep apnoea (CHOSA): a randomised, double-blind, placebo-controlled crossover trial
  1. Yasmina Serinel1,2,
  2. Brendon J Yee1,2,3,
  3. Ronald R Grunstein1,2,3,
  4. Keith H Wong1,2,3,
  5. Peter A Cistulli2,4,
  6. Hisatomi Arima5,6,
  7. Craig L Phillips1,2,4
  1. 1NHMRC 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
  2. 2Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia
  3. 3Department of Respiratory and Sleep Medicine, Royal Prince Alfred Hospital, Newtown, New South Wales, Australia
  4. 4Department of Respiratory and Sleep Medicine, Royal North Shore Hospital, Sydney, New South Wales, Australia
  5. 5The George Institute for Global Health, Sydney, New South Wales, Australia
  6. 6Department of Preventive Medicine and Public Health, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
  1. Correspondence to Dr Yasmina Serinel, CIRUS, Centre for Sleep and Chronobiology, Woolcock Institute, 431 Glebe Pt Rd, Glebe, NSW 2037, Australia; yasmina.serinel{at}


Background 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.

Methods 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.

Results 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).

Conclusions 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.

Trial registration number ACTRN12611000216910, Results.

  • Sleep apnoea

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  • Contributors CLP, RRG, HA and PAC were responsible for the conception and design of the study. YS and CLP were responsible for the acquisition of data. YS, BJY and KHW were responsible for medical management of patients in the trial. YS, KHW and CLP performed the statistical analyses. All authors contributed to the interpretation of data, drafting and revising of the article and final approval of article.

  • Funding This study was funded by the Australian National Health and Medical Research Council Grant number 632758. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. We received support from the pharmaceutical company Servier, who supplied us with both the active and placebo perindopril medication used in this study. CLP received an Australian National Health and Medical Research Council Career Development Fellowship (#1061545) and the Sydney Medical School Foundation Chapman Fellowship, which contributed to the completion of this work. RRG received an Australian National Health and Medical Research Council People Support Scheme, Practitioner Fellowship (#1022730), which contributed to the completion of this work. YS received a postgraduate scholarship from the University of Sydney to complete this work.

  • Competing interests None declared.

  • Ethics approval Northern Sydney Human Research Ethics Committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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