OSA remains a risk factor for cardiac events even in hypertensive patients under treatment: The UROSAH data

OSA remains a risk factor for cardiac events even in hypertensive patients under treatment: The UROSAH data | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article OSA remains a risk factor for cardiac events even in hypertensive patients under treatment: The UROSAH data Xiaoguang Yao, Nanfang Li, Mulalibieke Heizhati, Yingchun Wang, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2315028/v2 This work is licensed under a CC BY 4.0 License Status: Posted Version 2 posted You are reading this latest preprint version Show more versions Abstract Objectives: Both obstructive sleep apnea (OSA) and hypertension are risk factors of cardiovascular diseases (CVDs). The study aimed to observe the effect of the coexistence of OSA and hypertension on CVDs and evaluate the impact of antihypertensive treatment on CVDs outcomes in this population. Study Design: This is a retrospective cohortstudy. Methods: Hypertensive patients who underwent polysomnography (PSG) test in Jan 2011 to Dec 2013 were enrolled. OSA was defined as apnea hypopnea index(AHI)≥ 5. Outcomes were extended major adverse cardiovascular and cerebrovascular events (MACCE), including the first occurrence of non-fatal myocardial infarction, non-fatal stroke, revascularization, cardiac rehospitalization due to unstable angina or heart failure and all-cause death. The effect of the coexistence of OSA and hypertension on MACCE was explored by Cox regression analysis. Results: Overall, 415 individuals out of 3329 hypertensives experienced extended MACCE. At a median follow-up of 7.0 years, the incidence of extended MACCE was significantly higher in OSA group than in non-OSA group (hazard ratio [HR]: 1.59; 95% confidence interval [CI]:1.27-1.99; P<0.001). Totally, OSA patients had a 57% increased risk of cardiac events than subjects without OSA [HR(95%CI):1.57 (1.04-2.39), P=0.034] and the association did not change in further sensitivity analysis. Especially in uncontrolled hypertension, OSA showed a 93% increased risk of cardiac events compared to patients without OSA(P=0.036) . Conclusion: OSA remains a risk factor of cardiac events, while the association between OSA and cardiac events would be attenuated by the pharmacological-induced blood pressure control. Health sciences/Cardiology Health sciences/Medical research Health sciences/Risk factors obstructive sleep apnea hypertension major adverse cardiovascular and cerebrovascular events antihypertensive treatment Figures Figure 1 Introduction Obstructive sleep apnea (OSA) is one of the most common sleep disorders characterized by recurrent partial or complete cessation of breathing during sleep, affecting 1 billion adults aged 35–69 years globally. 1 Numerous observational and prospective studies have proved the association between OSA and cardiovascular diseases (CVDs) (eg, heart failure [HF], stroke, coronary heart disease, and atrial fibrillation) and all-cause mortality. 2 – 5 . Besides the health consequences, untreated OSA has also been associated with a substantial financial burden on patients, the healthcare system, and society. 6 Both OSA and hypertension are well-known CVD risk factors, with a strong bidirectional association between OSA and hypertension. 7 The co-occurrence of OSA and hypertension may significantly increase the risk of CVDs. 8 However, to date, the impact of the co-occurrence of OSA and hypertension on the risk of CVD outcomes has not been extensively studied. Especially, the data as to the outcomes of OSA in Asian population is not too much. For patients with hypertension, effective antihypertensive therapy can reduce the incidence of cardiovascular events. 9 , 10 However, as one of the effective methods to treat OSA, c ontinuous positive airway pressure (CPAP) is recommended for patients with OSA and hypertension besides antihypertensive drugs i n clinical practice. However, many early randomized controlled trials (RCTs) have shown a mild reduction in blood pressure (BP) (mean 2–4 mm Hg) with treatment by CPAP in OSA patients. 11 – 14 Recent large-scale studies have failed to observe the benefit of CPAP therapy in reducing the incidence of cardiovascular events in patients with OSA and CVDs, which questions the prognostic value of OSA in patients with cardiovascular risk factors. 15 – 17 In an 8-week randomized control study, antihypertensive medication has induced a 4-fold higher decrease in mean 24-hour BP compared to CPAP in untreated hypertensive patients with OSA, 18 That study suggested that antihypertensive drugs might have more potent cardiovascular protection than CPAP therapy in patients with hypertension and OSA. However, the residual effect of OSA on long-term CVDs in patients under antihypertensive treatment has been rarely explored. Therefore, this study aimed to evaluate the impact of the coexistence of OSA and hypertension on the incidence of cardiovascular events in hypertensive patients receiving antihypertensive treatment. Methods Study design and subjects Urumqi Research on Sleep Apnea and Hypertension (UROSAH) was conducted in the Hypertension Center of People’s Hospital of Xinjiang Uygur Autonomous Region, a provincial tertiary hospital that provides individualized hypertension treatment and identification of secondary hypertension. 19 UROSAH was a single-center observational study assessing the association between OSA and long-term CVDs in patients with hypertension. Hypertensive patients aged ≥ 18 years who visited the hypertension center between Jan 2011 and Dec 2013 were reviewed. The inclusion and exclusion criteria have been described in our previous study. 20 All inpatients were assessed for BP level, target organ damage, complications, and screening of secondary hypertension. In-laboratory full-night polysomnography (PSG) examination was performed. Finally, all patients were given individualized treatment, including lifestyle modification suggestions, medication regimens, and/or OSA-specific therapy (ie, oral appliance and CPAP treatment if necessary). Finally, 3329 inpatients were enrolled. This study was approved by the Ethics Committee of the People’s Hospital of Xinjiang Uygur Autonomous Region and was conducted according to the Declaration of Helsinki. Written informed consent was obtained from all patients or their legal relatives prior to study. Baseline information recording Baseline information collection included demographics, medication history, laboratory test results, and echocardiographic evaluation results. The details of information collection have been described in our previous study. 20 Diagnosis of hypertension Hypertension was defined as the resting blood pressure (BP) of at least 140/90 mmHg or the current use of antihypertensive drugs. Controlled hypertension was defined as systolic BP (SBP) of < 140 mmHg and diastolic BP (DBP) of < 90 mmHg after antihypertensive treatment. Uncontrolled hypertension was defined as SBP of ≥ 140 mmHg and/or DBP of ≥ 90 mmHg under antihypertensive treatment. Overnight sleep study and diagnosis of OSA All patients underwent in-laboratory overnight PSG (Compumedics E series, Australia) examination. Detailed information on PSG has been described in our previous studies. 21 OSA was defined as an apnea-hypopnea index (AHI) of ≥ 5 events per hour. Follow-up and outcomes All patients were followed up, and all clinical outcomes were collected via inpatient medical records, outpatient visits, or telephone calls. Additionally, data on the latest BP level and treatment of OSA (ie, CPAP) after the initial diagnosis were collected. For each patient, follow-up time was calculated from the baseline date and accrued until a CVD incident. The deadline for follow-up was Jan 2021. The primary outcomes in the study were extended major adverse cardiovascular and cerebrovascular events (MACCE), which included a newly-diagnosed MACCE and all-cause death during the study period. MACCE included death from heart and cerebrovascular disease, non-fatal myocardial infarction (MI), non-fatal stroke (including transient ischemic attack [TIA]), revascularization, and cardiac rehospitalization because of unstable angina or HF. Further, cardiac events included death from heart, non-fatal myocardial infarction (MI), revascularization, and cardiac rehospitalization because of unstable angina or HF. All endpoints were defined according to the proposed definitions by the Standardized Data Collection for Cardiovascular Trials Initiative. 22 If MACCE was not diagnosed in our hospital, the patients were asked to provide diagnosis and treatment data. For a sudden death case, the cause of death was asked from bereaved relatives and verified by the hospital death certificate, local police system, or hospitalization data. The international classification of diseases (ICD-10) classification code was used to classify 75 cases of deadly diseases. All clinical events were confirmed by medical documentation and identified by the clinical event committee of our hospital. Finally, 3329 patients were enrolled for the data analysis (Supplementary Fig. 1). Statistical analysis Categorical variables were presented as observed numbers and percentages and compared using Pearson Chi-square test among the groups. Continuous variables were reported as mean ± standard deviation (SD) if normally distributed and as the median and interquartile range (IQR) if not normally distributed. Differences between two groups for normally distributed continuous variables were compared using the independent samples t-test, and Mann–Whitney U test was used for non-normally distributed continuous variables. The cumulative incidence of primary outcomes was estimated by Kaplan–Meier survival curves, and Log-rank test was used to estimate the difference between patients with and without OSA. Multivariable Cox proportional hazard models were performed to identify independent predictors for extended MACCE and its components adjusted for factors known to influence MACCE in the whole population and subgroups stratified by BP control. Sensitivity analysis was performed in patients without OSA-specific treatment (ie, CPAP, oral appliance, and surgery) to exclude the potential benefit of OSA treatment. The impact of hypertension and OSA on the incidence of extended MACCE and cardiac events was assessed and adjusted for confounders as well. Data were analyzed using SPSS statistical software (version 25.0, SPSS Inc, Chicago, IL, USA), and all analyses were two-tailed. A P value of < 0.05 was considered statistically significant. Results Baseline characteristics of the subjects Of all participants, 77.6% (2585/3329) were diagnosed with OSA, the proportion of severity of mild, moderate and severe OSA was 37.9%(981/2585), 32.1%(829/2585) and 30.0% (775/2585), respectively. The overall mean age was 48.6 years, and 80.9% of patients were aged 30–60 years. The mean age, body mass index (BMI), serum estimated glomerular filtration rate (eGFR), low-density lipoprotein cholesterol (LDL)-c, and AHI of patients with OSA were significantly higher than in those without OSA, while the mean oxygen saturation (SaO 2 ) and nadir SaO 2 in the OSA group were much lower than that of patients without OSA. The constituent ratio of males, type 2 diabetes, coronary heart disease, and smokers in the OSA group was significantly higher than that in patients without OSA. Additionally, the proportion of ≥ 3 antihypertensive drugs, lipid-modifying agents, and antiplatelet drugs was greater in the OSA group. During the follow-up (median: 7.0 years), the crude incidence of overall outcomes was 18.8 per 1000 person-years in the total population, 20.6 per 1000 person-years in the OSA group, and 13.2 per 1000 person-years in patients without OSA (Table 1 ). Table 1 Baseline characteristics of the subjects Total subjects (n = 3329) OSA (n = 2585) without OSA (n = 744) P value Age(yr) 48.6 ± 11.0 49.7 ± 10.8 44.8 ± 10.8 < 0.001 Gender(Male,%) 2184(65.6) 1775(68.7) 409(55.0) < 0.001 BMI(kg/m 2 ) 27.6(25.4–30.1) 28.1(25.9–30.6) 26.2(24.2–28.7) < 0.001 Baseline office SBP(mmHg) 139.6 ± 19.5 140.0 ± 19.8 138.4 ± 18.5 0.046 Baseline office DBP(mmHg) 91.7 ± 13.8 91.7 ± 14.1 91.8 ± 12.9 0.820 Baseline MAP(mmHg) 107.7 ± 14.5 107.8 ± 14.7 107.3 ± 13.6 0.452 Smoker(n,%) 1099(33.0) 906(35.0) 193(25.9) < 0.001 GGT (mmol/L) 28.4 ± 22.3 28.6 ± 20.4 27.5 ± 27.9 0.217 GOT(mmol/L) 22.2 ± 14.2 22.4 ± 14.5 21.6 ± 12.8 0.171 eGFR(ml/min/1.73m 2 ) 96.8 ± 21.9 100.2 ± 21.8 95.9 ± 21.9 < 0.001 LDL-C(mmol/L) 2.61 ± 0.79 2.63 ± 0.80 2.54 ± 0.78 0.006 Total sleep time(mins) 390.2 ± 51.7 389.8 ± 50.8 391.4 ± 54.7 0.510 Sleep efficiency(%) 73.5 ± 9.6 73.6 ± 9.6 73.0 ± 9.5 0.169 AHI(event/h) 14.4(5.6–26.9) 19.7(10.7–32.2) 1.7(0.7–3.1) < 0.001 Mean SaO 2 (%) 93.0(91.0–94.0) 92.0(91.0–94.0) 94.0(93.0–95.0) < 0.001 Nadir SaO 2 (%) 82.0(77.0–86.0) 80.0(75.0–84.0) 88.0(87.0–90.0) < 0.001 Diabetes(%) 550(16.5) 478(18.5) 72(9.7) < 0.001 CHD(%) 373(11.2) 317(12.3) 56(7.5) < 0.001 Antihypertensive regimen(n,%) 0–1 drug 1183(35.5) 845(32.7) 338(45.4) < 0.001 2 drugs combination 1660(49.9) 1327(51.3) 333(44.8) ≥3 drugs combination 486(14.6) 413(15.8) 73(9.8) Lipid-modifying agents (n,%) 2070(62.2) 1693(65.5) 377(50.7) < 0.001 Antiplatelet drugs (n,%) 1639(49.2) 1348(52.1) 291(39.1) < 0.001 Antidiabetic drugs use in patients with DM2(n,%) 442(80.4) 383(80.1) 59(81.9) 0.717 Regular CPAP treatment(%) 0 114(4.4%) 0 Follow-up, median(IQR),y 7.0(6.0–8.1) 6.9(6.0–8.0) 7.3(6.3–8.1) Person-years followed,y 22016.15 16932.46 5083.69 - Total primary endpoints(n) 415 348 67 - Outcome per 1000 person-years 18.8 20.6 13.2 - MACCE incidence In total, 415 individuals experienced extended MACCE at the follow-up (median: 7.0 years). The incidence of extended MACCE was significantly higher in the OSA group than in the non-OSA group (hazard ratio [HR]: 1.59; 95% confidence interval [CI]: 1.27–1.99; P < 0.001, Fig. 1 A), and the same applied to cardiac events (HR [95% CI]: 2.44 [1.80–3.29], P < 0.001, Fig. 1 D). However, the incidence of all-cause death(Fig. 1 B) and stroke(Fig. 1 C) between the OSA and non-OSA groups was not significant. OSA and extended MACCE and cardiac events Table 2 presents the association between OSA and extended MACCE, as well as cardiac events, in the total population. In the crude model, OSA was shown as a risk factor for extended MACCE and cardiac events. Adjusted for confounders, no significant association between OSA and extended MACCE was observed. Still, OSA patients had a 57% increased risk of cardiac events compared with subjects without OSA (HR [95% CI]: 1.57 [1.04–2.39], P = 0.034), and the association did not change in a further sensitivity analysis. However, no association between OSA and stroke and all-cause death in the total population was observed (Table S1). Table 2 Baseline characteristics of the subjects Extended MACCE Cardiac events Model HR(95%CI) P value HR(95%CI) P value Crude model 1.59(1.23–2.07) 0.001 2.44(1.63–3.68) < 0.001 Partially adjusted model 1.24(0.95–1.61) 0.117 1.83(1.21–2.76) 0.004 Fully adjusted model 1.11(0.84–1.45) 0.461 1.57(1.04–2.39) 0.034 Sensitivity analysis 1.07(0.81–1.40) 0.645 1.53(1.01–2.33) 0.046 OSA and BP status The interaction between OSA status and BP level (≥ 140/90 mmHg or < 140/90 mmHg) was not significant for extended MACCE (HR [95% CI]: 1.12 [0.91–1.36], P = 0.287) or cardiac events (HR [95% CI]: 1.15 [0.88–1.50], P = 0.321) (Table S2), indicating that there was independent effect of OSA and BP on extended MACCE and cardiac events. In the uncontrolled hypertension population, OSA had a 1.93-fold increased risk of cardiac events compared to patients without OSA (P = 0.036) after adjustment for confounders. Further sensitivity analysis also showed OSA as a significant risk factor for cardiac events regardless of OSA-specific treatment. In contrast, in the controlled hypertension, OSA showed a 1.23-fold higher risk of cardiac events in the OSA group than in those without OSA, and as adjusted for confounding factors, the P value did not reach statistical significance (P = 0.489). However, no significant association between OSA and extended MACCE, stroke, and all-cause death was observed neither in the controlled hypertension nor in the uncontrolled hypertension group (Table 3 , Table S3). Table 3 Baseline characteristics of the subjects BP controlled < 140/90 mmHg BP controlled ≥ 140/90 mmHg Model adjusted HR(95%CI) P value adjusted HR(95%CI) P value Extended MACCE Crude model 1.60(1.06–2.42) 0.027 1.56(1.08–2.25) 0.017 Partially adjusted model 1.21(0.79–1.84) 0.377 1.28(0.88–1.86) 0.200 Fully adjusted model 1.01(0.66–1.56) 0.957 1.22(0.83–1.78) 0.310 Sensitivity analysis 0.96(0.62–1.48) 0.853 1.17(0.80–1.72) 0.411 Cardiac events Crude model 2.10(1.19–3.69) 0.010 2.50(1.38–4.54) 0.003 Partially adjusted model 1.52(0.86–2.67) 0.151 1.96(1.07–3.59) 0.029 Fully adjusted model 1.23(0.69–2.19) 0.489 1.93(1.04–3.57) 0.036 Sensitivity analysis 1.18(0.66–2.11) 0.580 1.89(1.02–3.49) 0.044 Discussion Our study was conducted in a hypertensive population with high OSA prevalence, showing that OSA remained a risk factor for cardiac events rather than extended MACCE, although all patients received antihypertensive treatment. However, the association between OSA and cardiac events might be attenuated by pharmacological BP control. Numerous studies have shown the association between OSA and MACCE or its components. However, the impact of OSA and hypertension co-occurrence on the risk of CVDs has not been extensively studied. Recently, a prospective cohort study, named Diastolic Chronic Heart Failure Study (DIAST-CHF), has assessed the adverse effects of OSA on cardiovascular morbidity and mortality in patients with cardiovascular risk factors, 23 but it did not find a significant association, in which the effective pharmacological interventions and a limited number of severe OSA patients might have been the possible reasons. Similarly, all subjects in our study were prescribed individualized antihypertensive regimens after systemic evaluation of hypertension, and lipid-lowering drugs, antidiabetic drugs, and antiplatelet drugs were given if necessary. Hence, the association between OSA and MACCE/cardiac events might be underestimated due to pharmacological interventions. Nevertheless, we still observed a significant association between OSA and cardiac outcomes after adjustment for confounders, which further stressed that OSA is an undeniable risk factor for CVDs. It is widely known that effective BP control reduces CVD and total mortality. 10 In the present study, OSA had a 93% increase in the risk of cardiac events in uncontrolled hypertension, and the association did not change after the exclusion of patients receiving OSA-specific treatment. However, it showed a lower risk of OSA leading to cardiac events in controlled hypertension compared to that in uncontrolled hypertension (Table 3 ), suggesting that the association between OSA and cardiac events would be attenuated by pharmacological BP control, but the residual risk of OSA for cardiac events in controlled hypertension was not completely eliminated. Our data did not observe a significant interaction between OSA and BP levels regarding MACCE and its components, indicating an independent effect of OSA and hypertension on CVDs. Indeed, patients with OSA had a higher risk of cardiac events than those without OSA. A previous study provided evidence that OSA and hypertension had an additive role regarding the increase in blood levels of inflammatory markers for atherosclerosis and progression of carotid atherosclerosis. 24 Additionally, OSA leads to plaque instability, plaque vulnerability, and coronary artery calcification. 25 Hence, our results support that using CPAP along with other antihypertensive regimens is important in treating hypertension and reducing CVDs mortality. 26 There are some strengths of our study despite it being a retrospective cohort study. First, there are many methods to diagnose or screen OSA in clinical work, such as PSG, home sleep apnea testing (HSAT), signs and symptoms, scoring scales (such as the Berlin questionnaire, Epworth score, and STOP-Bang questionnaire), and clinical prediction models (eg. the morphological prediction model), but the gold standard for diagnosis is PSG. 27 Nevertheless, the questionnaires and/or HSAT are generally used to define the status of OSA in many large-scale epidemic studies. Furthermore, well-designed questionnaires have shown low specificity and can be susceptible to bias in determining OSA. 28 In our study, all patients underwent standard PSG to identify OSA, which provided a more accurate diagnosis of OSA than questionnaires or home monitoring devices and added methodological rigor. Second, our study provided information on the impact of OSA on CVDs in young-to-middle-aged hypertensive patients. Previous studies on this topic have been mostly conducted in the elderly population(age > 60 years) and had small scale and/or short follow-up. 23 , 29 Our results enhanced the necessity of OSA detection and treatment in young-to-middle-aged hypertensive patients. Third, we also showed a higher incidence of extended MACCE in the total cohort and OSA patients compared to previous observational studies. 30 , 31 One of the reasons is that most patients in our cohort were at high risk of CVDs, who had additional cardiometabolic disorders as comorbidities, such as obesity and diabetes. Hence, the residual risk of OSA might have been increased in terms of contributing to the occurrence of cardiac events. The other reason is that although all patients with severe OSA were initially recommended the treatment with CPAP as soon as they were diagnosed, a substantial proportion of patients refused the treatment, and the treatment effect of OSA on MACCE was not discussed further due to low utilization of CPAP. Nonetheless, these patients were followed up in our hypertension center and provided information on the natural history of untreated OSA. Some limitations should be discussed. A substantial proportion of patients were suspected of having OSA, and the detection rate of OSA was very high. However, more than half of the patients were referred from different districts and regions of Xinjiang, which might have attenuated the population selection bias. In addition, our results come from hypertensive patients, a highly selected population who are at high risk of CVDs; thus, the conclusions should be cautiously generalized to the community. Finally, the medication adherence, as well as the control of metabolic disorders, was not fully assessed except for BP. The positive association between OSA and cardiac events might have been contaminated by poorly controlled known CVDs risk factors, which need further prospective verification studies. Conclusion OSA remains a risk factor for cardiac events rather than extended MACCE. However, the association between OSA and cardiac events would be attenuated by the pharmacological BP control. Abbreviations OSA, obstructive sleep apnea; HF, heart failure; CVD, cardiovascular disease; CPAP, continuous positive airway pressure; RCT, randomized controlled trial; UROSAH, Urumqi Research on Sleep Apnea and Hypertension; PSG, polysomnography; BP, blood pressure; SBP, systolic blood pressure; DBP, diastolic blood pressure; AHI, apnea-hypopnea index; MACCE, major adverse cardiovascular and cerebrovascular events; MI, myocardial infarction; TIA, transient ischemic attack; ICD-10, International Classification of Diseases, 10 th version; SD, standard deviation; IQR, interquartile range; BMI, body mass index; eGFR, estimated glomerular filtration rate; LDL-c, low-density lipoprotein cholesterol; SaO 2 , oxygen saturation; HR, hazard ratio; CI, confidence interval; DIAST-CHF, Diastolic Chronic Heart Failure Study; HSAT, home sleep apnea testing; Declarations Acknowledgments The authors appreciate Suofeiya Abulikemu, Guijuan Chang, Keming Zhou, Mei Cao, Nuerguli Maimaiti, Lei Wang, Wen Jiang, Guoliang Wang, Jing Hong, Le Sun, Mengyue Lin, Lin Gan and all the staffs of the Hypertension Center of People’s Hospital of Xinjiang for their support with the medical examinations and demographic data collection. Author Contributions Statement XG Yao and NF Li wrote the main manuscript text, M Heizhati prepared figures. YC Wang, Y Ma and R Wang collected the data, DL Zhang, Q Luo, JL Hu and MH Wang revised the manuscript, Q Zhu guided the statistics analysis. All authors reviewed the manuscript. Funding The study was supported by the Open project of Key Laboratory of Science and Technology Department of Xinjiang Uygur Autonomous Region (Grant No.2022D04024). Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author Prof. Nanfang Li on reasonable request. Ethical approval Ethics Committee of the People’s Hospital of Xinjiang Uygur Autonomous Region. Consent for publication Not applicable. Conflicts of Interest The authors declare that they have no conflicts of interest. 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J Am Med Assoc. 2012;307 (20): 2161–2168. doi: 10.1001/jama.2012.4366 Peker Y, Glantz H, Eulenburg C, Wegscheider K, Herlitz J, Thunström E. Effect of positive airway pressure on cardiovascular outcomes in coronary artery disease patients with nonsleepy obstructive sleep apnea. The RICCADSA randomized controlled trial. Am J Respir Crit Care Med 2016;194 (5): 613–620. https://doi.org/10.1164/rccm.201601-0088OC . Pépin JL, Tamisier R, Barone-Rochette G, Launois SH, Lévy P, Baguet JP. Comparison of continuous positive airway pressure and valsartan in hypertensive patients with sleep apnea. Am J Respir Crit Care Med 2010;182: 954–960. https://doi.org/10.1164/rccm.200912-1803OC . Wang L, Li N, Yao X, Chang G, Zhang D, Heizhati M, Wang M, Luo Q, Kong J. Detection of secondary causes and coexisting diseases in hypertensive patients: OSA and PA are the common causes associated with hypertension. Biomed Res Int 2017; 2017: 8295010. https://doi.org/10.1155/2017/8295010 . Cai X, Li N, Hu J, Wen W, Yao X, Zhu Q, Heizhati M, Hong J, Sun L, Tuerxun G, Zhang D, Luo Q. Nonlinear Relationship between Chinese visceral adiposity index and new-onset myocardial infarction in patients with hypertension and obstructive sleep spnoea: Insights from a cohort study. J Inflamm Res. 2022;15:687–700. https://doi.org/10.2147/JIR.S351238 Liang S, Li N, Heizhati M, Yao X, Abdireim A, Wang Y, Abulikemu Z, Zhang D, Chang G, Kong J, Zhou L, Hong J, Ying T, Zhang Y. What do changes in concentrations of serum surfactant proteins A and D in OSA mean? Sleep Breath 2015;19:955–962. https://doi.org/10.1007/s11325-014-1106-6 Hicks KA, Tcheng JE, Bozkurt B, Chaitman BR, Cutlip DE, Farb A, Fonarow GC, Jacobs JP, Jaff MR, Lichtman JH, Limacher MC, Mahaffey KW, Mehran R, Nissen SE, Smith EE, Targum SL. 2014 ACC/AHA key data elements and definitions for cardiovascular endpoint events in clinical trials: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Data Standards (Writing Committee to Develop Cardiovascular Endpoints Data Standards). J Am Coll Cardiol 2015;66:403–469. https://doi.org/10.1016/j.jacc.2014.12.018 . Haarmann H, Koch J, Bonsch N, Mende M, Werhahn SM, Lüers C, Stahrenberg R, Edelmann F, Holzendorf V, von Haehling S, Pieske B, Andreas S, Lüthje L, Wachter R. Morbidity and mortality in patients with cardiovascular risk factors and obstructive sleep apnoea: results from the DIAST-CHF cohort. Respir Med 2019; 154: 127–132. https://doi.org/10.1016/j.rmed.2019.06.019 Damiani MF, Zito A, Carratù P, Falcone VA, Bega E, Scicchitano P, Ciccone MM, Resta O. Obstructive Sleep Apnea, Hypertension, and Their Additive Effects on Atherosclerosis. Biochem Res Int 2015; 2015: 984193. https://doi.org/10.1155/2015/984193 Shah NA, Yaggi HK, Concato J, Mohsenin V. Obstructive sleep apnea as a risk factor for coronary events or cardiovascular death. Sleep Breath 2010;14:131–136. https://doi.org/10.1007/s11325-009-0298-7 Jehan S, Zizi F, Pandi-Perumal SR, McFarlane SI, Jean-Louis G, Myers AK. Obstructive sleep apnea, hypertension, resistant hypertension and cardiovascular disease. Sleep Med Disord 2020; 4(3): 67–76. PMID: 33501418; PMCID: PMC7830712. Kapur VK, Auckley DH, Chowdhuri S, Kuhlmann DC, Mehra R, Ramar K, Harrod CG. Clinical practice guideline for diagnostic testing for adult obstructive sleep apnea: an American academy of sleep medicine clinical practice guideline. J Clin Sleep Med 2017; 13(3):479–504. https://doi.org/10.5664/jcsm.6506 Xu H., Zhao X., Shi Y, Xinyi L, Yingjun Q, Jianyin Z, Hongliang Y, Hengye H, Jian G, Shankai Y. Development and validation of a simple-to-use clinical nomogram for predicting obstructive sleep apnea . BMC Pulm Med 2019;19,18. https://doi.org/10.1186/s12890-019-0782-1 Wuxiang X, Fanfan Z, Xiaoyu S. Obstructive sleep apnea and serious adverse outcomes in patients with cardiovascular or cerebrovascular disease: a PRISMA- compliant systematic review and meta-analysis. Medicine (Baltimore) 2014; 93: e336. doi: 10.1097/MD.0000000000000336 Polonis K, Sompalli S, Becari C, Xie J, Covassin N, Schulte PJ, Druliner BR, Johnson RA, Narkiewicz K, Boardman LA, Singh P, Somers VK. Telomere Length and Risk of Major Adverse Cardiac Events and Cancer in Obstructive Sleep Apnea Patients. Cells 2019; 8(5):381. https://doi.org/10.3390/cells8050381 Yuan X, Fang J, Wang L, Yao L, Li L, Zhan X, Wu H, Pinto JM, Wei Y. Adequate continuous positive airway pressure therapy reduces mortality in Chinese patients with obstructive sleep apnea. Sleep Breath 2015;19, 911–920 (2015). https://doi.org/10.1007/s11325-014-1091-9 Additional Declarations No competing interests reported. Supplementary Files supplementarytables123.doc Cite Share Download PDF Status: Posted Version 2 posted You are reading this latest preprint version Show more versions Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2315028","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":169829387,"identity":"b6d2de6a-1a4e-49f9-8ba8-270408800aef","order_by":0,"name":"Xiaoguang Yao","email":"","orcid":"","institution":"Hypertension Center of People’s Hospital of Xinjiang Uygur Autonomous Region","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xiaoguang","middleName":"","lastName":"Yao","suffix":""},{"id":169829388,"identity":"52409c40-1754-40b4-a897-97f335634329","order_by":1,"name":"Nanfang Li","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA70lEQVRIiWNgGAWjYBACPhBRAcT8zIyNDz4wSBDWwgYizgCxZHtzs+EMkrQYnDneJsxDjMPYpJufPThQc8eu4UZiG7PNH4s8/gbmh49u4NMic8zc4MCxZ8mNMxLbHue2SRRLHGAzNs7Bp0UiwUz6A9vhZGaJxHbj3AaJxIYDPGzS+LWkf5M48O9wMptEYpu0xR+JxPmEteSYSRxsO2zHw3OwTRrITdxAhJYyiYN9hxMk2BubDXvbJBI3HibgF36J9G0SB74dtrc/zP7wwY8/dYnzjjc/fIxPCwwkNsCZzEQoBwF7ItWNglEwCkbBSAQALs1PMpI7qVIAAAAASUVORK5CYII=","orcid":"","institution":"Hypertension Center of People’s Hospital of Xinjiang Uygur Autonomous Region","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Nanfang","middleName":"","lastName":"Li","suffix":""},{"id":169829389,"identity":"5f54fe25-10a7-4636-8c6f-ebbaacdecd67","order_by":2,"name":"Mulalibieke Heizhati","email":"","orcid":"","institution":"Hypertension Center of People’s Hospital of Xinjiang Uygur Autonomous 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10:44:16","currentVersionCode":2,"declarations":"","doi":"10.21203/rs.3.rs-2315028/v2","doiUrl":"https://doi.org/10.21203/rs.3.rs-2315028/v2","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":32016990,"identity":"dd8e7273-13e3-442e-be1b-cfed324be9eb","added_by":"auto","created_at":"2023-01-24 22:00:36","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":214672,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier curve of cardiovascular events. Proportion of patients with a cardiovascular events for patients with OSA and without OSA. *OSA: obstructive sleep apnea\u003c/p\u003e\n\u003cp\u003eA. Cumulative incidence of extended MACCE; \u0026nbsp;B. Cumulative incidence of all-cause death; C. Cumulative incidence of stoke; \u0026nbsp;D. Cumulative incidence of cardiac events.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-2315028/v2/5d52a175f22663511a36bace.jpeg"},{"id":38936019,"identity":"5d4f42a4-8a73-4451-a29f-c370c61fe5a1","added_by":"auto","created_at":"2023-06-22 15:59:43","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":587623,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2315028/v2/7d868950-168c-45c6-ba42-f9908fa8e191.pdf"},{"id":32016989,"identity":"f483fe2f-0de0-430a-9d66-8b0ef5bda13d","added_by":"auto","created_at":"2023-01-24 22:00:36","extension":"doc","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":180736,"visible":true,"origin":"","legend":"","description":"","filename":"supplementarytables123.doc","url":"https://assets-eu.researchsquare.com/files/rs-2315028/v2/3f43dd1b499d6e413094f59f.doc"}],"financialInterests":"No competing interests reported.","formattedTitle":"OSA remains a risk factor for cardiac events even in hypertensive patients under treatment: The UROSAH data","fulltext":[{"header":"Introduction","content":"\u003cp\u003eObstructive sleep apnea (OSA) is one of the most common sleep disorders characterized by recurrent partial or complete cessation of breathing during sleep, affecting 1\u0026nbsp;billion adults aged 35\u0026ndash;69 years globally.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Numerous observational and prospective studies have proved the association between OSA and cardiovascular diseases (CVDs) (eg, heart failure [HF], stroke, coronary heart disease, and atrial fibrillation) and all-cause mortality.\u003csup\u003e\u003cspan additionalcitationids=\"CR3 CR4\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. Besides the health consequences, untreated OSA has also been associated with a substantial financial burden on patients, the healthcare system, and society.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eBoth OSA and hypertension are well-known CVD risk factors, with a strong bidirectional association between OSA and hypertension.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e The co-occurrence of OSA and hypertension may significantly increase the risk of CVDs.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e However, to date, the impact of the co-occurrence of OSA and hypertension on the risk of CVD outcomes has not been extensively studied. Especially, the data as to the outcomes of OSA in Asian population is not too much.\u003c/p\u003e \u003cp\u003eFor patients with hypertension, effective antihypertensive therapy can reduce the incidence of cardiovascular events.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e However, as one of the effective methods to treat OSA, \u003cb\u003ec\u003c/b\u003eontinuous positive airway pressure (CPAP) is recommended for patients with OSA and hypertension besides antihypertensive drugs \u003cb\u003ei\u003c/b\u003en clinical practice. However, many early randomized controlled trials (RCTs) have shown a mild reduction in blood pressure (BP) (mean 2\u0026ndash;4 mm Hg) with treatment by CPAP in OSA patients.\u003csup\u003e\u003cspan additionalcitationids=\"CR12 CR13\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e Recent large-scale studies have failed to observe the benefit of CPAP therapy in reducing the incidence of cardiovascular events in patients with OSA and CVDs, which questions the prognostic value of OSA in patients with cardiovascular risk factors.\u003csup\u003e\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e In an 8-week randomized control study, antihypertensive medication has induced a 4-fold higher decrease in mean 24-hour BP compared to CPAP in untreated hypertensive patients with OSA,\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e That study suggested that antihypertensive drugs might have more potent cardiovascular protection than CPAP therapy in patients with hypertension and OSA. However, the residual effect of OSA on long-term CVDs in patients under antihypertensive treatment has been rarely explored. Therefore, this study aimed to evaluate the impact of the coexistence of OSA and hypertension on the incidence of cardiovascular events in hypertensive patients receiving antihypertensive treatment.\u003c/p\u003e "},{"header":"Methods","content":"\u003cdiv id=\"Sec2\" class=\"Section2\"\u003e\u003cdiv id=\"Sec3\" class=\"Section3\"\u003e \u003ch2\u003eStudy design and subjects\u003c/h2\u003e \u003cp\u003eUrumqi Research on Sleep Apnea and Hypertension (UROSAH) was conducted in the Hypertension Center of People\u0026rsquo;s Hospital of Xinjiang Uygur Autonomous Region, a provincial tertiary hospital that provides individualized hypertension treatment and identification of secondary hypertension.\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e UROSAH was a single-center observational study assessing the association between OSA and long-term CVDs in patients with hypertension. Hypertensive patients aged\u0026thinsp;\u0026ge;\u0026thinsp;18 years who visited the hypertension center between Jan 2011 and Dec 2013 were reviewed. The inclusion and exclusion criteria have been described in our previous study.\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e All inpatients were assessed for BP level, target organ damage, complications, and screening of secondary hypertension. In-laboratory full-night polysomnography (PSG) examination was performed. Finally, all patients were given individualized treatment, including lifestyle modification suggestions, medication regimens, and/or OSA-specific therapy (ie, oral appliance and CPAP treatment if necessary). Finally, 3329 inpatients were enrolled. This study was approved by the Ethics Committee of the People\u0026rsquo;s Hospital of Xinjiang Uygur Autonomous Region and was conducted according to the Declaration of Helsinki. Written informed consent was obtained from all patients or their legal relatives prior to study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section3\"\u003e \u003ch2\u003eBaseline information recording\u003c/h2\u003e \u003cp\u003eBaseline information collection included demographics, medication history, laboratory test results, and echocardiographic evaluation results. The details of information collection have been described in our previous study.\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section3\"\u003e \u003ch2\u003eDiagnosis of hypertension\u003c/h2\u003e \u003cp\u003eHypertension was defined as the resting blood pressure (BP) of at least 140/90 mmHg or the current use of antihypertensive drugs. Controlled hypertension was defined as systolic BP (SBP) of \u0026lt;\u0026thinsp;140 mmHg and diastolic BP (DBP) of \u0026lt;\u0026thinsp;90 mmHg after antihypertensive treatment. Uncontrolled hypertension was defined as SBP of \u0026ge;\u0026thinsp;140 mmHg and/or DBP of \u0026ge;\u0026thinsp;90 mmHg under antihypertensive treatment.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section3\"\u003e \u003ch2\u003eOvernight sleep study and diagnosis of OSA\u003c/h2\u003e \u003cp\u003eAll patients underwent in-laboratory overnight PSG (Compumedics E series, Australia) examination. Detailed information on PSG has been described in our previous studies.\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e OSA was defined as an apnea-hypopnea index (AHI) of \u0026ge;\u0026thinsp;5 events per hour.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section3\"\u003e \u003ch2\u003eFollow-up and outcomes\u003c/h2\u003e \u003cp\u003eAll patients were followed up, and all clinical outcomes were collected via inpatient medical records, outpatient visits, or telephone calls. Additionally, data on the latest BP level and treatment of OSA (ie, CPAP) after the initial diagnosis were collected. For each patient, follow-up time was calculated from the baseline date and accrued until a CVD incident. The deadline for follow-up was Jan 2021. The primary outcomes in the study were extended major adverse cardiovascular and cerebrovascular events (MACCE), which included a newly-diagnosed MACCE and all-cause death during the study period. MACCE included death from heart and cerebrovascular disease, non-fatal myocardial infarction (MI), non-fatal stroke (including transient ischemic attack [TIA]), revascularization, and cardiac rehospitalization because of unstable angina or HF. Further, cardiac events included death from heart, non-fatal myocardial infarction (MI), revascularization, and cardiac rehospitalization because of unstable angina or HF. All endpoints were defined according to the proposed definitions by the Standardized Data Collection for Cardiovascular Trials Initiative.\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e If MACCE was not diagnosed in our hospital, the patients were asked to provide diagnosis and treatment data. For a sudden death case, the cause of death was asked from bereaved relatives and verified by the hospital death certificate, local police system, or hospitalization data. The international classification of diseases (ICD-10) classification code was used to classify 75 cases of deadly diseases. All clinical events were confirmed by medical documentation and identified by the clinical event committee of our hospital. Finally, 3329 patients were enrolled for the data analysis (Supplementary Fig.\u0026nbsp;1).\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eCategorical variables were presented as observed numbers and percentages and compared using Pearson Chi-square test among the groups. Continuous variables were reported as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD) if normally distributed and as the median and interquartile range (IQR) if not normally distributed. Differences between two groups for normally distributed continuous variables were compared using the independent samples t-test, and Mann\u0026ndash;Whitney U test was used for non-normally distributed continuous variables. The cumulative incidence of primary outcomes was estimated by Kaplan\u0026ndash;Meier survival curves, and Log-rank test was used to estimate the difference between patients with and without OSA. Multivariable Cox proportional hazard models were performed to identify independent predictors for extended MACCE and its components adjusted for factors known to influence MACCE in the whole population and subgroups stratified by BP control. Sensitivity analysis was performed in patients without OSA-specific treatment (ie, CPAP, oral appliance, and surgery) to exclude the potential benefit of OSA treatment. The impact of hypertension and OSA on the incidence of extended MACCE and cardiac events was assessed and adjusted for confounders as well. Data were analyzed using SPSS statistical software (version 25.0, SPSS Inc, Chicago, IL, USA), and all analyses were two-tailed. A P value of \u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eBaseline characteristics of the subjects\u003c/h2\u003e \u003cp\u003eOf all participants, 77.6% (2585/3329) were diagnosed with OSA, the proportion of severity of mild, moderate and severe OSA was 37.9%(981/2585), 32.1%(829/2585) and 30.0% (775/2585), respectively. The overall mean age was 48.6 years, and 80.9% of patients were aged 30\u0026ndash;60 years. The mean age, body mass index (BMI), serum estimated glomerular filtration rate (eGFR), low-density lipoprotein cholesterol (LDL)-c, and AHI of patients with OSA were significantly higher than in those without OSA, while the mean oxygen saturation (SaO\u003csub\u003e2\u003c/sub\u003e) and nadir SaO\u003csub\u003e2\u003c/sub\u003e in the OSA group were much lower than that of patients without OSA. The constituent ratio of males, type 2 diabetes, coronary heart disease, and smokers in the OSA group was significantly higher than that in patients without OSA. Additionally, the proportion of \u0026ge;\u0026thinsp;3 antihypertensive drugs, lipid-modifying agents, and antiplatelet drugs was greater in the OSA group. During the follow-up (median: 7.0 years), the crude incidence of overall outcomes was 18.8 per 1000 person-years in the total population, 20.6 per 1000 person-years in the OSA group, and 13.2 per 1000 person-years in patients without OSA (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics of the subjects\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal subjects\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;3329)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOSA\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;2585)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ewithout OSA\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;744)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge(yr)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e48.6\u0026thinsp;\u0026plusmn;\u0026thinsp;11.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e49.7\u0026thinsp;\u0026plusmn;\u0026thinsp;10.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e44.8\u0026thinsp;\u0026plusmn;\u0026thinsp;10.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender(Male,%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2184(65.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1775(68.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e409(55.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI(kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27.6(25.4\u0026ndash;30.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28.1(25.9\u0026ndash;30.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e26.2(24.2\u0026ndash;28.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBaseline office SBP(mmHg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e139.6\u0026thinsp;\u0026plusmn;\u0026thinsp;19.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e140.0\u0026thinsp;\u0026plusmn;\u0026thinsp;19.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e138.4\u0026thinsp;\u0026plusmn;\u0026thinsp;18.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.046\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBaseline office DBP(mmHg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e91.7\u0026thinsp;\u0026plusmn;\u0026thinsp;13.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e91.7\u0026thinsp;\u0026plusmn;\u0026thinsp;14.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e91.8\u0026thinsp;\u0026plusmn;\u0026thinsp;12.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.820\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBaseline MAP(mmHg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e107.7\u0026thinsp;\u0026plusmn;\u0026thinsp;14.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e107.8\u0026thinsp;\u0026plusmn;\u0026thinsp;14.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e107.3\u0026thinsp;\u0026plusmn;\u0026thinsp;13.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.452\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoker(n,%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1099(33.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e906(35.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e193(25.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGGT (mmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28.4\u0026thinsp;\u0026plusmn;\u0026thinsp;22.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28.6\u0026thinsp;\u0026plusmn;\u0026thinsp;20.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e27.5\u0026thinsp;\u0026plusmn;\u0026thinsp;27.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.217\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGOT(mmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22.2\u0026thinsp;\u0026plusmn;\u0026thinsp;14.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22.4\u0026thinsp;\u0026plusmn;\u0026thinsp;14.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21.6\u0026thinsp;\u0026plusmn;\u0026thinsp;12.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.171\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eeGFR(ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e96.8\u0026thinsp;\u0026plusmn;\u0026thinsp;21.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e100.2\u0026thinsp;\u0026plusmn;\u0026thinsp;21.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e95.9\u0026thinsp;\u0026plusmn;\u0026thinsp;21.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLDL-C(mmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.61\u0026thinsp;\u0026plusmn;\u0026thinsp;0.79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.63\u0026thinsp;\u0026plusmn;\u0026thinsp;0.80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.54\u0026thinsp;\u0026plusmn;\u0026thinsp;0.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.006\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal sleep time(mins)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e390.2\u0026thinsp;\u0026plusmn;\u0026thinsp;51.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e389.8\u0026thinsp;\u0026plusmn;\u0026thinsp;50.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e391.4\u0026thinsp;\u0026plusmn;\u0026thinsp;54.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.510\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSleep efficiency(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e73.5\u0026thinsp;\u0026plusmn;\u0026thinsp;9.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e73.6\u0026thinsp;\u0026plusmn;\u0026thinsp;9.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e73.0\u0026thinsp;\u0026plusmn;\u0026thinsp;9.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.169\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAHI(event/h)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14.4(5.6\u0026ndash;26.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19.7(10.7\u0026ndash;32.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.7(0.7\u0026ndash;3.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean SaO\u003csub\u003e2\u003c/sub\u003e(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e93.0(91.0\u0026ndash;94.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e92.0(91.0\u0026ndash;94.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e94.0(93.0\u0026ndash;95.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNadir SaO\u003csub\u003e2\u003c/sub\u003e(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e82.0(77.0\u0026ndash;86.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e80.0(75.0\u0026ndash;84.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e88.0(87.0\u0026ndash;90.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiabetes(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e550(16.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e478(18.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e72(9.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCHD(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e373(11.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e317(12.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e56(7.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntihypertensive regimen(n,%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u0026ndash;1 drug\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1183(35.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e845(32.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e338(45.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2 drugs combination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1660(49.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1327(51.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e333(44.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;3 drugs combination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e486(14.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e413(15.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e73(9.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLipid-modifying agents (n,%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2070(62.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1693(65.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e377(50.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntiplatelet drugs (n,%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1639(49.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1348(52.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e291(39.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntidiabetic\u0026nbsp;drugs use in patients with DM2(n,%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e442(80.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e383(80.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e59(81.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.717\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRegular CPAP treatment(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e114(4.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFollow-up, median(IQR),y\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.0(6.0\u0026ndash;8.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.9(6.0\u0026ndash;8.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7.3(6.3\u0026ndash;8.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePerson-years followed,y\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22016.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16932.46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5083.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal primary endpoints(n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e415\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e348\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOutcome per 1000 person-years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section3\"\u003e \u003ch2\u003eMACCE incidence\u003c/h2\u003e \u003cp\u003eIn total, 415 individuals experienced extended MACCE at the follow-up (median: 7.0 years). The incidence of extended MACCE was significantly higher in the OSA group than in the non-OSA group (hazard ratio [HR]: 1.59; 95% confidence interval [CI]: 1.27\u0026ndash;1.99; P\u0026thinsp;\u0026lt;\u0026thinsp;0.001, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA), and the same applied to cardiac events (HR [95% CI]: 2.44 [1.80\u0026ndash;3.29], P\u0026thinsp;\u0026lt;\u0026thinsp;0.001, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eD). However, the incidence of all-cause death(Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB) and stroke(Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC) between the OSA and non-OSA groups was not significant.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section3\"\u003e \u003ch2\u003eOSA and extended MACCE and cardiac events\u003c/h2\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e presents the association between OSA and extended MACCE, as well as cardiac events, in the total population. In the crude model, OSA was shown as a risk factor for extended MACCE and cardiac events. Adjusted for confounders, no significant association between OSA and extended MACCE was observed. Still, OSA patients had a 57% increased risk of cardiac events compared with subjects without OSA (HR [95% CI]: 1.57 [1.04\u0026ndash;2.39], P\u0026thinsp;=\u0026thinsp;0.034), and the association did not change in a further sensitivity analysis. However, no association between OSA and stroke and all-cause death in the total population was observed (Table S1).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics of the subjects\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eExtended MACCE\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eCardiac events\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eModel\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHR(95%CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHR(95%CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCrude model\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.59(1.23\u0026ndash;2.07)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.44(1.63\u0026ndash;3.68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePartially adjusted model\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.24(0.95\u0026ndash;1.61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.117\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.83(1.21\u0026ndash;2.76)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFully adjusted model\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.11(0.84\u0026ndash;1.45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.461\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.57(1.04\u0026ndash;2.39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.034\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSensitivity analysis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.07(0.81\u0026ndash;1.40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.645\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.53(1.01\u0026ndash;2.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.046\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section3\"\u003e \u003ch2\u003eOSA and BP status\u003c/h2\u003e \u003cp\u003eThe interaction between OSA status and BP level (\u0026ge;\u0026thinsp;140/90 mmHg or \u0026lt;\u0026thinsp;140/90 mmHg) was not significant for extended MACCE (HR [95% CI]: 1.12 [0.91\u0026ndash;1.36], P\u0026thinsp;=\u0026thinsp;0.287) or cardiac events (HR [95% CI]: 1.15 [0.88\u0026ndash;1.50], P\u0026thinsp;=\u0026thinsp;0.321) (Table S2), indicating that there was independent effect of OSA and BP on extended MACCE and cardiac events. In the uncontrolled hypertension population, OSA had a 1.93-fold increased risk of cardiac events compared to patients without OSA (P\u0026thinsp;=\u0026thinsp;0.036) after adjustment for confounders. Further sensitivity analysis also showed OSA as a significant risk factor for cardiac events regardless of OSA-specific treatment. In contrast, in the controlled hypertension, OSA showed a 1.23-fold higher risk of cardiac events in the OSA group than in those without OSA, and as adjusted for confounding factors, the P value did not reach statistical significance (P\u0026thinsp;=\u0026thinsp;0.489). However, no significant association between OSA and extended MACCE, stroke, and all-cause death was observed neither in the controlled hypertension nor in the uncontrolled hypertension group (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, Table S3).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics of the subjects\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eBP controlled\u0026thinsp;\u0026lt;\u0026thinsp;140/90 mmHg\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eBP controlled\u0026thinsp;\u0026ge;\u0026thinsp;140/90 mmHg\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eModel\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eadjusted HR(95%CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eadjusted HR(95%CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExtended MACCE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCrude model\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.60(1.06\u0026ndash;2.42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.027\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.56(1.08\u0026ndash;2.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.017\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePartially adjusted model\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.21(0.79\u0026ndash;1.84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.377\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.28(0.88\u0026ndash;1.86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.200\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFully adjusted model\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.01(0.66\u0026ndash;1.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.957\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.22(0.83\u0026ndash;1.78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.310\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSensitivity analysis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.96(0.62\u0026ndash;1.48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.853\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.17(0.80\u0026ndash;1.72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.411\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCardiac events\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCrude model\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.10(1.19\u0026ndash;3.69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.010\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.50(1.38\u0026ndash;4.54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePartially adjusted model\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.52(0.86\u0026ndash;2.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.151\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.96(1.07\u0026ndash;3.59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.029\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFully adjusted model\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.23(0.69\u0026ndash;2.19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.489\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.93(1.04\u0026ndash;3.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.036\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSensitivity analysis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.18(0.66\u0026ndash;2.11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.580\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.89(1.02\u0026ndash;3.49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.044\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur study was conducted in a hypertensive population with high OSA prevalence, showing that OSA remained a risk factor for cardiac events rather than extended MACCE, although all patients received antihypertensive treatment. However, the association between OSA and cardiac events might be attenuated by pharmacological BP control.\u003c/p\u003e \u003cp\u003eNumerous studies have shown the association between OSA and MACCE or its components. However, the impact of OSA and hypertension co-occurrence on the risk of CVDs has not been extensively studied. Recently, a prospective cohort study, named Diastolic Chronic Heart Failure Study (DIAST-CHF), has assessed the adverse effects of OSA on cardiovascular morbidity and mortality in patients with cardiovascular risk factors,\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e but it did not find a significant association, in which the effective pharmacological interventions and a limited number of severe OSA patients might have been the possible reasons. Similarly, all subjects in our study were prescribed individualized antihypertensive regimens after systemic evaluation of hypertension, and lipid-lowering drugs, antidiabetic drugs, and antiplatelet drugs were given if necessary. Hence, the association between OSA and MACCE/cardiac events might be underestimated due to pharmacological interventions. Nevertheless, we still observed a significant association between OSA and cardiac outcomes after adjustment for confounders, which further stressed that OSA is an undeniable risk factor for CVDs.\u003c/p\u003e \u003cp\u003eIt is widely known that effective BP control reduces CVD and total mortality.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e In the present study, OSA had a 93% increase in the risk of cardiac events in uncontrolled hypertension, and the association did not change after the exclusion of patients receiving OSA-specific treatment. However, it showed a lower risk of OSA leading to cardiac events in controlled hypertension compared to that in uncontrolled hypertension (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e), suggesting that the association between OSA and cardiac events would be attenuated by pharmacological BP control, but the residual risk of OSA for cardiac events in controlled hypertension was not completely eliminated.\u003c/p\u003e \u003cp\u003eOur data did not observe a significant interaction between OSA and BP levels regarding MACCE and its components, indicating an independent effect of OSA and hypertension on CVDs. Indeed, patients with OSA had a higher risk of cardiac events than those without OSA. A previous study provided evidence that OSA and hypertension had an additive role regarding the increase in blood levels of inflammatory markers for atherosclerosis and progression of carotid atherosclerosis.\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e Additionally, OSA leads to plaque instability, plaque vulnerability, and coronary artery calcification.\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e Hence, our results support that using CPAP along with other antihypertensive regimens is important in treating hypertension and reducing CVDs mortality.\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThere are some strengths of our study despite it being a retrospective cohort study. First, there are many methods to diagnose or screen OSA in clinical work, such as PSG, home sleep apnea testing (HSAT), signs and symptoms, scoring scales (such as the Berlin questionnaire, Epworth score, and STOP-Bang questionnaire), and clinical prediction models (eg. the morphological prediction model), but the gold standard for diagnosis is PSG.\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e Nevertheless, the questionnaires and/or HSAT are generally used to define the status of OSA in many large-scale epidemic studies. Furthermore, well-designed questionnaires have shown low specificity and can be susceptible to bias in determining OSA.\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e In our study, all patients underwent standard PSG to identify OSA, which provided a more accurate diagnosis of OSA than questionnaires or home monitoring devices and added methodological rigor. Second, our study provided information on the impact of OSA on CVDs in young-to-middle-aged hypertensive patients. Previous studies on this topic have been mostly conducted in the elderly population(age\u0026thinsp;\u0026gt;\u0026thinsp;60 years) and had small scale and/or short follow-up.\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e,\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e Our results enhanced the necessity of OSA detection and treatment in young-to-middle-aged hypertensive patients. Third, we also showed a higher incidence of extended MACCE in the total cohort and OSA patients compared to previous observational studies.\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e,\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e One of the reasons is that most patients in our cohort were at high risk of CVDs, who had additional cardiometabolic disorders as comorbidities, such as obesity and diabetes. Hence, the residual risk of OSA might have been increased in terms of contributing to the occurrence of cardiac events. The other reason is that although all patients with severe OSA were initially recommended the treatment with CPAP as soon as they were diagnosed, a substantial proportion of patients refused the treatment, and the treatment effect of OSA on MACCE was not discussed further due to low utilization of CPAP. Nonetheless, these patients were followed up in our hypertension center and provided information on the natural history of untreated OSA.\u003c/p\u003e \u003cp\u003eSome limitations should be discussed. A substantial proportion of patients were suspected of having OSA, and the detection rate of OSA was very high. However, more than half of the patients were referred from different districts and regions of Xinjiang, which might have attenuated the population selection bias. In addition, our results come from hypertensive patients, a highly selected population who are at high risk of CVDs; thus, the conclusions should be cautiously generalized to the community. Finally, the medication adherence, as well as the control of metabolic disorders, was not fully assessed except for BP. The positive association between OSA and cardiac events might have been contaminated by poorly controlled known CVDs risk factors, which need further prospective verification studies.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eOSA remains a risk factor for cardiac events rather than extended MACCE. However, the association between OSA and cardiac events would be attenuated by the pharmacological BP control.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eOSA, obstructive sleep apnea;\u003c/p\u003e\n\u003cp\u003eHF, heart failure;\u003c/p\u003e\n\u003cp\u003eCVD, cardiovascular disease;\u003c/p\u003e\n\u003cp\u003eCPAP, continuous positive airway pressure;\u003c/p\u003e\n\u003cp\u003eRCT, randomized controlled trial;\u003c/p\u003e\n\u003cp\u003eUROSAH, Urumqi Research on Sleep Apnea and Hypertension;\u003c/p\u003e\n\u003cp\u003ePSG, polysomnography;\u003c/p\u003e\n\u003cp\u003eBP, blood pressure;\u003c/p\u003e\n\u003cp\u003eSBP, systolic blood pressure;\u003c/p\u003e\n\u003cp\u003eDBP, diastolic blood pressure;\u003c/p\u003e\n\u003cp\u003eAHI, apnea-hypopnea index;\u003c/p\u003e\n\u003cp\u003eMACCE, major adverse cardiovascular and cerebrovascular events;\u003c/p\u003e\n\u003cp\u003eMI, myocardial infarction;\u003c/p\u003e\n\u003cp\u003eTIA, transient ischemic attack;\u003c/p\u003e\n\u003cp\u003eICD-10, International Classification of Diseases, 10\u003csup\u003eth\u003c/sup\u003e version;\u003c/p\u003e\n\u003cp\u003eSD, standard deviation;\u003c/p\u003e\n\u003cp\u003eIQR, interquartile range;\u003c/p\u003e\n\u003cp\u003eBMI, body mass index;\u003c/p\u003e\n\u003cp\u003eeGFR, estimated glomerular filtration rate;\u003c/p\u003e\n\u003cp\u003eLDL-c, low-density lipoprotein cholesterol;\u003c/p\u003e\n\u003cp\u003eSaO\u003csub\u003e2\u003c/sub\u003e, oxygen saturation;\u003c/p\u003e\n\u003cp\u003eHR, hazard ratio;\u003c/p\u003e\n\u003cp\u003eCI, confidence interval;\u003c/p\u003e\n\u003cp\u003eDIAST-CHF, Diastolic Chronic Heart Failure Study;\u003c/p\u003e\n\u003cp\u003eHSAT, home sleep apnea testing;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors appreciate Suofeiya Abulikemu, Guijuan Chang, Keming Zhou, Mei Cao, Nuerguli Maimaiti, Lei Wang, Wen Jiang, Guoliang Wang, Jing Hong, Le Sun, Mengyue Lin, Lin Gan and all the staffs of the Hypertension Center of People\u0026rsquo;s Hospital of Xinjiang for their support with the medical examinations and demographic data collection.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eXG Yao and NF Li wrote the main manuscript text, \u0026nbsp; M Heizhati prepared figures. YC Wang, Y Ma and R Wang collected the data, DL Zhang, Q Luo, JL Hu and MH Wang revised the manuscript, Q Zhu guided the statistics analysis. All authors reviewed the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was supported by the Open project of \u0026nbsp;Key Laboratory of Science and Technology Department of Xinjiang Uygur Autonomous Region (Grant No.2022D04024).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author Prof.\u0026nbsp;Nanfang Li\u0026nbsp;on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthics Committee of the People\u0026rsquo;s Hospital of Xinjiang Uygur Autonomous Region.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no conflicts of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBenjafield Adam V., Ayas Najib T., Eastwood Peter R., Heinzer Raphael., Ip Mary S M., Morrell Mary J., Nunez Carlos M., Patel Sanjay R., Penzel \u003cb\u003eThomas\u003c/b\u003e., \u003cb\u003eP\u0026eacute;pin\u003c/b\u003e Jean-Louis., Peppard Paul \u003cb\u003eE\u003c/b\u003e., \u003cb\u003eSinha Sanjeev\u003c/b\u003e., \u003cb\u003eTufik Sergio\u003c/b\u003e., \u003cb\u003eValentine Kate\u003c/b\u003e., \u003cb\u003eMalhotra Atul\u003c/b\u003e. \u003cb\u003eEstimation of the global prevalence and burden of obstructive sleep apnoea\u003c/b\u003e: \u003cb\u003ea literature\u003c/b\u003e-\u003cb\u003ebased analysis\u003c/b\u003e. \u0026lt;bi\u0026gt;Lancet Respir Med\u0026lt;/bi\u0026gt; 2019; \u003cb\u003e7\u003c/b\u003e: \u003cb\u003e687\u003c/b\u003e\u0026ndash;\u003cb\u003e698\u003c/b\u003e. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/S2213-2600(19)30198-5\u003c/span\u003e\u003cspan address=\"10.1016/S2213-2600(19)30198-5\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eConiglio AC, Mentz RJ. \u003cb\u003eSleep breathing disorders in heart failure\u003c/b\u003e. 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Obstructive sleep apnea and serious adverse outcomes in patients with cardiovascular or cerebrovascular disease: a PRISMA- compliant systematic review and meta-analysis. Medicine (Baltimore) 2014; 93: e336. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/MD.0000000000000336\u003c/span\u003e\u003cspan address=\"10.1097/MD.0000000000000336\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePolonis K, Sompalli S, Becari C, Xie J, Covassin N, Schulte PJ, Druliner BR, Johnson RA, Narkiewicz K, Boardman LA, Singh P, Somers VK. \u003cem\u003eTelomere Length and Risk of Major Adverse Cardiac Events and Cancer in Obstructive Sleep Apnea Patients.\u003c/em\u003e \u0026lt;bi\u0026gt;Cells\u0026lt;/bi\u0026gt; 2019; \u003cem\u003e8(5):381.\u003c/em\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3390/cells8050381\u003c/span\u003e\u003cspan address=\"10.3390/cells8050381\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYuan X, Fang J, Wang L, Yao L, Li L, Zhan X, Wu H, Pinto JM, Wei Y. Adequate continuous positive airway pressure therapy reduces mortality in Chinese patients with obstructive sleep apnea. \u0026lt;bi\u0026gt;Sleep Breath\u0026lt;/bi\u0026gt; 2015;19, 911\u0026ndash;920 (2015). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s11325-014-1091-9\u003c/span\u003e\u003cspan address=\"10.1007/s11325-014-1091-9\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"obstructive sleep apnea, hypertension, major adverse cardiovascular and cerebrovascular events, antihypertensive treatment","lastPublishedDoi":"10.21203/rs.3.rs-2315028/v2","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2315028/v2","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjectives:\u003c/strong\u003e Both obstructive sleep apnea (OSA) and hypertension are risk factors of cardiovascular diseases (CVDs). The study aimed to observe the effect of the coexistence of OSA and hypertension on CVDs and evaluate the impact of \u0026nbsp;antihypertensive treatment on CVDs outcomes in this population.\u003c/p\u003e\n\u003cp\u003eStudy Design: This is a \u0026nbsp;retrospective cohortstudy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e Hypertensive patients who underwent polysomnography (PSG) test in Jan 2011 to Dec 2013 were enrolled. OSA was defined as apnea hypopnea index(AHI)≥ 5. Outcomes were extended major adverse cardiovascular and cerebrovascular events (MACCE), including the first occurrence of non-fatal myocardial infarction, non-fatal stroke, revascularization, cardiac rehospitalization due to unstable angina or heart failure and all-cause death. The effect of the coexistence of OSA and hypertension on MACCE was explored by Cox regression analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eOverall, 415 individuals out of 3329 hypertensives experienced extended MACCE. At a median follow-up of 7.0 years, the incidence of extended MACCE was significantly higher in OSA group than in non-OSA group (hazard ratio [HR]: 1.59; 95% confidence interval [CI]:1.27-1.99; P\u0026lt;0.001). Totally, OSA patients had a 57% increased risk of cardiac events than subjects without OSA [HR(95%CI):1.57 (1.04-2.39), P=0.034] and the association did not change in further sensitivity analysis. Especially in uncontrolled hypertension, OSA showed a 93% increased risk of cardiac events compared to patients without OSA(P=0.036) .\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e OSA remains a risk factor of cardiac events, while the association between OSA and cardiac events would be attenuated by the pharmacological-induced blood pressure control.\u003c/p\u003e","manuscriptTitle":"OSA remains a risk factor for cardiac events even in hypertensive patients under treatment: The UROSAH data","msid":"","msnumber":"","nonDraftVersions":[{"code":2,"date":"2023-01-24 22:00:31","doi":"10.21203/rs.3.rs-2315028/v2","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}},{"code":1,"date":"2022-11-29 23:36:53","doi":"10.21203/rs.3.rs-2315028/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"68e22b9f-08ba-46a8-863a-26b21e9eadb9","owner":[],"postedDate":"January 24th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":18610485,"name":"Health sciences/Cardiology"},{"id":18610486,"name":"Health sciences/Medical research"},{"id":18610487,"name":"Health sciences/Risk factors"}],"tags":[],"updatedAt":"2023-06-22T15:59:30+00:00","versionOfRecord":[],"versionCreatedAt":"2023-01-24 22:00:31","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v2","identity":"rs-2315028","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2315028","identity":"rs-2315028","version":["v2"]},"buildId":"ApUGefWb6u5IBVtyqm6d5","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}