A Cohort Study on Increasing Blood Pressure Benefits in Sleep Apnea Patients After CPAP Treatment
Conditions: Hypertension (HTN), Sleep Apnea Syndrome, Obstructive
Sponsor: Beijing Anzhen Hospital

Clinical research protocol
A Cohort Study on Increasing Blood Pressure Benefits in Sleep
Apnea Patients After CPAP Treatment
NCT Number: not yet assigned
Document Date: 2025-08-15

I. Research Background and Scientific Basis
Over the past few decades, the prevalence of hypertension among Chinese citizens has risen
significantly, with approximately 27.9% of adults currently affected by the condition1. Timely
intervention targeting factors that elevate blood pressure is crucial for delaying the progression of
hypertension and preventing cardiovascular and cerebrovascular diseases. Some patients with early
blood pressure abnormalities (130-139/80-89 mmHg) may prioritize lifestyle interventions.
Following effective non-pharmacological treatment, some patients achieve normal blood pressure
(below 120/80 mmHg), while others fail to normalize or even experience further increases.
Persistent elevated blood pressure may indicate that contributing factors remain unaddressed,
potentially rendering non-pharmacological approaches ineffective.
（1）The Therapeutic Effects of CPAP on Blood Pressure Abnormalities
Obstructive sleep apnea (OSA) is a highly prevalent respiratory disorder. Current estimates
indicate that approximately 176 million people in China suffer from OSA, with 67 million
classified as having moderate to severe OSA2. Numerous studies indicate that OSA is a significant
risk factor for hypertension3–5. Patients with OSA experience recurrent upper airway obstruction
during the night, which not only leads to intermittent hypoxemia but also causes autonomic
nervous system dysfunction. Excessive sympathetic nervous system activation at night results in
significant fluctuations in blood pressure within a short period6, even accompanied by a blunted
baroreflex response7. Simultaneously, OSA causes fragmented sleep and sleep deprivation at night,
leading to poor daytime alertness and mood in patients. This results in elevated sympathetic
activity throughout the day, causing a significant increase in daytime blood pressure8.
Continuous positive airway pressure (CPAP) is the primary treatment for moderate-to-severe
obstructive sleep apnea (OSA). It maintains upper airway patency through an “airway support”
mechanism, thereby eliminating respiratory events. Although numerous studies indicate that OSA
patients experience blood pressure benefits following CPAP therapy9–12, However, results from

numerous studies collectively indicate that the degree of blood pressure improvement following
CPAP therapy is not entirely satisfactory. For example, in a meta-analysis involving 1,904
patients12, Following CPAP therapy, daytime systolic and diastolic blood pressure decreased by
3.55 mmHg and 2.97 mmHg, respectively; nighttime systolic and diastolic blood pressure
decreased by 3.67 mmHg and 2.33 mmHg, respectively. Although the downward trend in blood
pressure was statistically significant, the magnitude of improvement was disappointing. Even in a
study published by Ou in 2024, blood pressure did not show significant improvement after 6
months of CPAP treatment13. Evidently, some hypertensive patients with combined OSA do not
experience blood pressure benefits following effective CPAP therapy. Investigating factors
influencing CPAP treatment outcomes is crucial for selecting suitable hypertensive patients for
CPAP therapy and tailoring individualized intervention approaches.
（2）Patients with OSA-related blood pressure fluctuations may be candidates for blood
pressure benefits from CPAP therapy
Patients with OSA often exhibit non-dipping blood pressure and elevated morning blood pressure.
Studies indicate that patients with OSA-induced blood pressure rhythm abnormalities are more
likely to benefit from CPAP therapy14,15. For example, studies by Pengo et al. confirm that OSA
patients with non-spoon-shaped blood pressure profiles experience significant blood pressure
reduction following CPAP therapy, whereas those with spoon-shaped blood pressure profiles show
minimal improvement in blood pressure after CPAP treatment14. Domestic scholars have found that
patients with significantly elevated pulse transit time (PTT)-blood pressure due to OSA experience
marked improvement in office blood pressure following CPAP therapy15. However, while PPT-BP
can reflect trends in blood pressure changes, its readings exhibit significant fluctuations and may
differ from actual blood pressure levels. This discrepancy is particularly noticeable in the
measurement of blood pressure troughs and peaks, where errors frequently occur16; Conventional
ambulatory blood pressure monitoring can only measure blood pressure intermittently, clearly
failing to capture the transient effects of respiratory events on blood pressure. Considering that

blood pressure may fluctuate dramatically within a short timeframe during sleep-related respiratory
events17, Developing reliable technology capable of continuously recording noninvasive blood
pressure holds significant value for identifying patients with OSA-related hypertension and
screening individuals who may benefit from CPAP therapy.
Our research group will employ novel volumetric clamping technology to precisely measure
beat-by-beat blood pressure18, Furthermore, by precisely integrating it with sleep parameters, we
developed a sleep-blood pressure index that accurately reflects blood pressure fluctuations during
respiratory events and explored its predictive value for CPAP treatment outcomes.
（3）Sleep aids may improve sleep quality and enhance CPAP compliance, potentially
increasing blood pressure benefits
Numerous studies indicate that CPAP usage duration is one of the most critical factors determining
cardiovascular benefits in patients with obstructive sleep apnea11,19. However, many OSA patients
also suffer from severe insomnia, making it difficult for them to tolerate CPAP therapy. At the same
time, some OSA patients experience a lowered arousal threshold after CPAP treatment20, Difficulty
falling asleep and early morning awakenings significantly impair CPAP treatment adherence.
Therefore, insomnia and awakenings may be factors affecting CPAP treatment compliance, thereby
reducing blood pressure benefits in OSA patients. Recent studies indicate that trazodone reduces
post-CPAP awakenings and improves CPAP treatment adherence21, Therefore, we hypothesize that
administering sleep aids to OSA patients experiencing insomnia and wakefulness may improve
sleep quality following CPAP therapy, enhance CPAP compliance, and potentially increase blood
pressure benefits.
This study will conduct a cohort analysis involving patients with early-stage blood pressure
abnormalities who have not received drug therapy, as well as hypertensive patients requesting
non-pharmacological blood pressure management.
The objectives are: ①to identify OSA patients likely to benefit from blood pressure control using

an innovative sleep-blood pressure index; ②to examine the impact of insomnia and arousal
following CPAP therapy on blood pressure; ③to enhance sleep quality with sleep aids, thereby
improving CPAP treatment adherence and blood pressure outcomes. This study will provide novel
insights and solutions to address the challenge of uncontrolled blood pressure following CPAP
therapy for OSA.
Reference
1.
Chinese Society of Cardiology, Chinese Medical Association; Hypertension Committee of
Cross-Straits Medicine Exchange Association; Cardiovascular Disease Prevention and
Rehabilitation Committee, Chinese Association of Rehabilitation Medicine. Zhonghua Xin Xue
Guan Bing Za Zhi. 2024;52(9):985-1032. doi:10.3760/cma.j.cn112148-20240709-00377
2.
Benjafield AV, Ayas NT, Eastwood PR, et al. Estimation of the global prevalence and burden
of obstructive sleep apnoea: A literature-based analysis. The Lancet Respiratory Medicine.
2019;7(8):687-698. doi:10.1016/S2213-2600(19)30198-5
3.
Shiina K. Obstructive sleep apnea -related hypertension: A review of the literature and clinical
management strategy. Hypertens Res. 2024;47(11):3085-3098. doi:10.1038/s41440-024-01852-y
4.
Sansom K, Reynolds A, Windred D, et al. The interrelationships between sleep regularity,
obstructive sleep apnea, and hypertension in a middle-aged community population. Sleep.
2024;47(3):zsae001. doi:10.1093/sleep/zsae001
5.
Wu H, Guo Y. Risk of resistant hypertension associated with insomnia in patients with
obstructive sleep apnea. Sleep Medicine. 2023;101:445-451. doi:10.1016/j.sleep.2022.12.001
6.
Pal A, Martinez F, Aguila AP, et al. Beat-to-beat blood pressure variability in patients with
obstructive sleep apnea. J Clin Sleep Med. 2021;17(3):381-392. doi:10.5664/jcsm.8866
7.
Pal A, Martinez F, Chatterjee R, et al. Baroreflex sensitivity during rest and pressor challenges
in obstructive sleep apnea patients with and without CPAP. Sleep Med. 2022;97:73-81.

doi:10.1016/j.sleep.2022.05.846
8.
Meng Z, Sun B, Chen W, Zhang X, Huang M, Xu J. Depression of non-neuronal cholinergic
system may play a role in co-occurrence of subjective daytime sleepiness and hypertension in
patients with obstructive sleep apnea syndrome. Nat Sci Sleep. 2021;13:2153-2163.
doi:10.2147/NSS.S339038
9.
Gottlieb DJ, Punjabi NM, Mehra R, et al. CPAP versus oxygen in obstructive sleep apnea. N
Engl J Med. 2014;370(24):2276-2285. doi:10.1056/NEJMoa1306766
10. Labarca G, Schmidt A, Dreyse J, et al. Efficacy of continuous positive airway pressure (CPAP)
in patients with obstructive sleep apnea (OSA) and resistant hypertension (RH): Systematic review
and meta-analysis. Sleep Med Rev. 2021;58:101446. doi:10.1016/j.smrv.2021.101446
11. Sánchez-de-la-Torre M, Gracia-Lavedan E, Benítez ID, et al. Long-term effect of obstructive
sleep apnea and continuous positive airway pressure treatment on blood pressure in patients with
acute coronary syndrome: A clinical trial. Ann Am Thorac Soc. 2022;19(10):1750-1759.
doi:10.1513/AnnalsATS.202203-260OC
12. Shang W, Zhang Y, Liu L, Chen F, Wang G, Han D. Benefits of continuous positive airway
pressure on blood pressure in patients with hypertension and obstructive sleep apnea: A
meta-analysis. Hypertens Res. 2022;45(11):1802-1813. doi:10.1038/s41440-022-00954-9
13. Ou YH, Colpani JT, Cheong CS, et al. Mandibular advancement vs CPAP for blood pressure
reduction in patients with obstructive sleep apnea. J Am Coll Cardiol. 2024;83(18):1760-1772.
doi:10.1016/j.jacc.2024.03.359
14. Pengo MF, Oscullo G, Gomez-Olivas JD, Bilo G, Parati G, Martinez-Garcia MA. Nocturnal
BP profile predicts CPAP effect on BP in patients with OSA and resistant hypertension. Chest.
2023;164(5):1302-1304. doi:10.1016/j.chest.2023.05.021
15. Meng Z, Chen Y, Yang T, et al. New perspective on exploring the predictive factors of blood

pressure reduction during CPAP treatment in people with severe OSA and hypertension: A
prospective observational study. BMJ Open Resp Res. 2023;10(1):e001560.
doi:10.1136/bmjresp-2022-001560
16. Hoshide S, Yoshihisa A, Tsuchida F, et al. Pulse transit time-estimated blood pressure: A
comparison of beat-to-beat and intermittent measurement. Hypertens Res. 2022;45(6):1001-1007.
doi:10.1038/s41440-022-00899-z
17. Cheng YB, Guo QH, Xia JH, et al. Obstructive sleep apnea in relation to beat-to-beat,
reading-to-reading, and day-to-day blood pressure variability. Hypertens Res.
2024;47(5):1391-1400. doi:10.1038/s41440-024-01628-4
18. Wu P, Bai Z, Xu L, et al. New approaches for rapid setpoint determination and uninterrupted
tracking in non-invasive continuous blood pressure monitoring based on volume-clamp method.
Biomedical Signal Processing And Control. 2023;86:105305. doi:10.1016/j.bspc.2023.105305
19. Labarca G, Schmidt A, Dreyse J, Jorquera J, Barbe F. Telemedicine interventions for CPAP
adherence in obstructive sleep apnea patients: Systematic review and meta-analysis. Sleep Med Rev.
2021;60:101543. doi:10.1016/j.smrv.2021.101543
20. Haba-Rubio J, Sforza E, Weiss T, Schröder C, Krieger J. Effect of CPAP treatment on
inspiratory arousal threshold during NREM sleep in OSAS. Sleep Breath. 2005;9(1):12-19.
doi:10.1007/s11325-005-0002-5
21. Schmickl CN, Lettieri CJ, Orr JE, et al. The arousal threshold as a drug target to improve
continuous positive airway pressure adherence: Secondary analysis of a randomized trial. Am J
Respir Crit Care Med. 2020;202(11):1592-1595. doi:10.1164/rccm.202003-0502LE

II. Research Objectives and Content
1. Research Objectives
1.1 Validate innovative sleep-blood pressure parameters for screening OSA patients who benefit
from blood pressure improvement after CPAP therapy.
1.2 Identify reasons for suboptimal blood pressure improvement in OSA patients after CPAP
therapy through analysis of treated patients.
1.3 Improve CPAP treatment compliance and enhance blood pressure benefits by administering
trazodone or zopiclone for insomnia and post-CPAP arousals (including micro-arousals).
2. Research Content
2.1 Screen OSA patients likely to benefit using an innovative sleep-blood pressure index: Develop
the sleep-blood pressure index by precisely measuring continuous blood pressure via novel
volumetric clamping technology and synchronizing it with PSG through engineering techniques.
Conduct a cohort study to analyze characteristics of patients with blood pressure improvement after
CPAP therapy, obtaining a sleep-blood pressure index and its cutoff value for predicting CPAP
treatment benefits.
2.2 Exploring Factors Influencing Blood Pressure Improvement After CPAP Therapy: Compare
differences in sleep-related parameters—including insomnia indices, arousal-related indices, and
autonomic function—between patients with and without blood pressure improvement after 3
months of CPAP therapy. Analyze residual sleep factors affecting CPAP efficacy.
2.3 Enhancing CPAP Compliance and Blood Pressure Benefits in OSA Patients: Select patients
with pre-CPAP insomnia or frequent post-CPAP arousals. Administer trazodone or zopiclone for 4
weeks alongside CPAP therapy. Demonstrate how sleep aids improve sleep quality in OSA patients,
thereby increasing CPAP compliance and enhancing blood pressure outcomes.
3. Distinctive Features and Innovations

3.1 Theoretical Innovation: Identifies and corrects reasons for unimproved blood pressure after
CPAP therapy, thereby increasing benefits for OSA patients.
3.2 Technical Innovation: Develops a sleep-blood pressure index through synchronized continuous
blood pressure and sleep monitoring, providing a new indicator for cardiovascular risk assessment
in OSA patients.
4. Key Scientific Questions:
Scientific Question 1: How can we predict which individuals are likely to benefit from CPAP
therapy before treatment initiation?
Solution: Administer an innovative sleep-blood pressure index to patients with moderate-to-severe
OSA and initiate CPAP therapy, demonstrating that the sleep-blood pressure index can predict
blood pressure improvement following CPAP treatment.
Scientific Question 2: Why is blood pressure improvement limited in OSA patients after CPAP
therapy?
Solution: Investigate the relationship between sleep parameters and clinical improvements
post-CPAP therapy, identifying insomnia and arousal as key factors limiting treatment benefits in
OSA patients.
Scientific Question 3: How can we enhance blood pressure benefits in OSA patients following
CPAP therapy?
Solution: Improve CPAP adherence by administering sleep aids to specific patient groups, thereby
increasing blood pressure benefits in OSA patients.

III. Research Protocol and Technical Approach
1. Study Design: Through a cohort study, this research aims to: ①explore innovative sleep-blood
pressure indices; ②elucidate factors influencing suboptimal blood pressure improvement
following CPAP therapy in OSA patients; ③determine whether sleep aids alleviate insomnia and
awakenings, thereby enhancing CPAP compliance and improving blood pressure.
2. Study Population: Participants will be recruited from the Sleep Medicine Center and
Hypertension Department of Anzhen Hospital.
(1) Inclusion Criteria:

Aged 18–70 years;

Diagnosed with obstructive sleep apnea (OSA) via overnight polysomnography (PSG),
meeting either: (a) AHI ≥5 events/hour with at least one of the following: (1) patient-reported
daytime sleepiness, unrefreshing sleep, fatigue, or insomnia; (2) sleep arousal due to gasping
or choking; (3) Reports from bed partners or witnesses of habitual snoring, breathing
interruptions, or both during sleep. Or (b) AHI ≥15 events/hour.

Blood pressure meeting any of the following criteria: (1) Office BP 120-139/80-89 mmHg
with ≤2 cardiovascular risk factors; (2) Newly diagnosed blood pressure 140-159/90-99
mmHg without cardiovascular risk factors; (3) Hypertensive patients with low cardiovascular
risk who are currently on stable antihypertensive medication but whose office blood pressure
does not meet normal blood pressure standards (120/80 mmHg); (4) Any non-high
cardiovascular risk patient who voluntarily requests three months of non-antihypertensive
medication therapy;

Able to tolerate 24-hour ambulatory blood pressure monitoring and continuous blood pressure
monitoring;

Understands and signs the informed consent form, voluntarily agrees to undergo 3 months of

CPAP therapy and participate in follow-up visits.
(2) Exclusion Criteria:

Previously diagnosed OSA currently undergoing treatment (CPAP, orthodontic appliances,
surgery, etc.);

Secondary hypertension caused by factors other than OSA, such as renal artery stenosis,
nephropathy, Cushing's syndrome, or primary aldosteronism;

Unstable medical condition (cardiovascular or cerebrovascular events or major surgery within
the past 3 months, severe hypersomnia [ESS ≥16 points] or cognitive impairment preventing
cooperation, active psychiatric illness, or substance/alcohol abuse);

Rheumatic/autoimmune diseases and malignancies;

Aortic diseases (e.g., giant cell arteritis, aortic dissection, aneurysms);

Conditions preventing accurate blood pressure measurement (e.g., atrial fibrillation, upper
limb vascular disease);

Familial early-onset hypertension;

Use of any prescription or over-the-counter sleep aids within 4 weeks prior to enrollment (e.g.,
benzodiazepines, non-benzodiazepine hypnotics, melatonin receptor agonists, trazodone,
sedative antidepressants/antipsychotics, sedative-containing OTC products);

Allergy or contraindication to potential study drugs (trazodone, zopiclone);

Pregnancy, lactation, or planned pregnancy;

Frequent night shift work (≥3 nights/week) or diagnosed circadian rhythm disorder;

Participation in other interventional clinical trials.
3. CPAP Intervention: Subjects undergo CPAP therapy in fixed pressure mode, with ≥4 hours of use

per night and ≥21 days of use per month. Prior to treatment initiation, subjects undergo overnight
automatic (or manual) pressure titration under PSG or overnight automatic pressure titration
without PSG, based on clinical condition, to select the optimal pressure achieving “optimal/good”
therapeutic effect (referencing the American Academy of Sleep Medicine's CPAP Treatment and
Titration Standards for Adult Obstructive Sleep Apnea). Investigators enhance subjects'
understanding of CPAP through educational outreach to overcome psychological barriers. During
follow-up, respiratory and otolaryngology specialists addressed specialty-related issues affecting
CPAP use, promptly resolving CPAP-related discomforts to enhance CPAP adherence.
4. Pharmacological Intervention: For patients with OSA and insomnia selected in Study
Component 3, or those experiencing frequent awakenings despite CPAP therapy, combined CPAP
and trazodone (or zopiclone) treatment was recommended. The treatment regimen involves taking
trazodone at an initial dose of 25-50 mg/night before bedtime. Based on patient tolerance and
efficacy, the dose may be increased by 25 mg every 3-5 days, not exceeding a maximum of 150
mg/night. Zopiclone should start at 3.75-7.5 mg/night, adjustable to 7.5 mg/night as appropriate.
The total treatment period was 4 weeks. Changes in subjective and objective sleep quality before
and after medication were recorded using questionnaires, actigraphs, and polysomnography.
During follow-up, patients were naturally grouped based on treatment choice and adherence: CPAP
alone, CPAP plus trazodone, trazodone alone, and untreated. Compare baseline-to-endpoint blood
pressure changes across groups, including intra-group comparisons and inter-group comparisons of
rate of change.
5. Sample Size Estimation: Based on the research team's preliminary findings, this project will
enroll 120 OSA patients receiving CPAP therapy (Research Content 1-2) and 80 patients with
insomnia combined with OSA or frequent awakenings during CPAP use (Research Content 3).

IV. Expected Outcomes and Evaluation Metrics
(1) Expected Results
1. The Sleep-Blood Pressure Index can predict the efficacy of blood pressure improvement
following CPAP therapy, identifying OSA patients likely to benefit from CPAP treatment.
2. Insomnia and awakenings (including micro-awakenings), along with the resulting sympathetic
overactivation, are key factors contributing to suboptimal blood pressure improvement after CPAP.
Trazodone and zopiclone improve sleep quality, reduce awakenings and blood pressure fluctuations
during CPAP therapy, thereby lowering daytime blood pressure values.
(2) Evaluation Metrics
1. Propose and validate an innovative sleep-blood pressure metric.
2. Publish two SCI papers (Q1 and Q2 journals).
This protocol strictly adheres to the Good Clinical Practice (GCP) guidelines and Anzhen
Hospital's Special Management Measures for High-Level Research. It integrates all technical
details of the application and has mitigated common risks of ethical rejection (funding disclosure,
vulnerable subject protection, and intervention rationale).