The association between blood pressure control and long-term cardiovascular outcomes in hypertension coexists with obstructive sleep apnea

doi:10.21203/rs.3.rs-3113620/v1

Download PDF

Research Article

The association between blood pressure control and long-term cardiovascular outcomes in hypertension coexists with obstructive sleep apnea

https://doi.org/10.21203/rs.3.rs-3113620/v1

This work is licensed under a CC BY 4.0 License

Journal Publication

published 21 Nov, 2023

Read the published version in BMC Cardiovascular Disorders →

You are reading this latest preprint version

Purpose: The goal of blood pressure (BP) control will be lower when hypertensive patients have comorbidities that can affect the risk of cardiovascular diseases. But, the goal of BP control for hypertensive patients who coexists with obstructive sleep apnea (OSA) is not discussed, which is a special population at high risk of cardiovascular diseases.

Patients and methods: Using data from the UROSAH Study, we enrolled 3267 participants who were diagnosed with hypertension and performed polysomnography during 2011-2013 to explore the association between BP control and long-term major adverse cardiovascular and cerebrovascular events (MACCEs). Outcomes of interest were the levels of BP control, MACCEs, cardiac events and cerebrovascular events. Then we calculated the cumulative incidence of MACCEs and performed Cox proportional hazards with stepwise models.

Results: 379 of 3267 patients experienced MACCEs during a median follow-up of 7.0 years. After full risk adjustment, BP control of 120-140/80-90mmHg was associated with the lowest risk of cerebrovascular events (HR: 0.53, 95%CI:0.35-0.82) rather than MACCEs and cardiac events in the total cohort. The association did not changed much in patients with OSA. When the SBP and DBP were discussed separately, the SBP control of 120-140mmHg or <120 mmHg was associated with the decreased incidence of MACCEs and cerebrovascular events. When DBP control<80 mmHg, the risk of cerebrovascular events showed 54% decrease[(HR:0.46, 95%CI: 0.25-0.88)] in patients with hypertension and OSA.

Conclusion: In this retrospective study, antihypertensive-drug-induced BP control at 120-140/80-90mmHg showed possible beneficial effect on incident MACCEs. However, SBP≤120mmHg or DBP<80mmHg respectively showed the significant benefit to reduce incident cerebrovascular events in hypertensives with OSA.

obstructive sleep apnea

diastolic blood pressure

major adverse cardiovascular and cerebrovascular events

stroke

Obstructive sleep apnea (OSA) is a disorder characterized by recurrent episodes of upper airway obstruction during sleep, resulting in chronic intermittent hypoxia and sleep fragmentation. OSA is widely accepted as one of the most important causes of secondary hypertension, even though the hypertension may not necessarily be a consequence of the OSA. 30–50% of hypertensive patients will have comorbid OSA^[1]. Moreover, there is evidence that the BP can only be mildly decreased(2-4mmHg) after treatment with continuous positive airway pressure (CPAP) in OSA patients coexisted with hypertension^[2]. Besides hypertension, OSA is a common cardiovascular risk factor and related to coronary heart disease, heart failure, stroke, and et al^[3]. Nowadays, there are more than 1.2 billion patients with hypertension and nearly 1 billion patients with OSA gloablly^[4]. It can be seen that both OSA and hypertension are not only common conditions, but often coexist. Thus, the individuals with hypertension and OSA are special population that needs more attention, considering that both are known risk factors for cardiovascular and cerebrovascular diseases.

The pathophysiological changes caused by OSA, such as the intermittent hypoxia, hypercoagulable state^[5], excessive mechanical stress on the heart and large artery walls that are caused by strong intrathoracic pressure changes, and the repetitive BP rises by arousal-induced reflex sympathetic activation^[6] may greatly affect the perfusion pressure of coronary artery and cerebrovascular, therefore, it is suspected that untreated OSA patients may need higher blood pressure control to have cardiovascular protection. However, there is no relevant evidence for this currently.

It is known that the antihypertensive goals are lower when hypertensive patients have comorbidities that can affect cardiovascular risk and treatment strategies^[7]. However, this principle has been less verified in hypertensive patients with OSA. Moreover, an previous 8-week RCT has shown that valsartan induced a four-fold decrease in mean 24-hour BP than CPAP did in untreated hypertensive patients with OSA^[8], suggesting that antihypertensive drugs are more helpful for OSA patients with hypertension to control BP, but the long-term benefit of BP control for CVDs outcomes in OSA has not been evaluated. Therefore, the aim of this study was to explore the possible goal of BP control via evaluating the association between BP control and the long-term cardiovascular consequences of the coexistence of hypertension and OSA.

Study design and subjects

All subjects are from Urumqi Research on Sleep Apnea and Hypertension (UROSAH) study, which is a single-center retrospective cohort study. The inclusion and exclusion criteria has been described in our previous study^[9]. At baseline, all subjects completed medical history collection and had height, weight, BP measurement, and overnight polysomnography (PSG) test.

This study was conducted according to the Declaration of Helsinki and approved by the Ethics Committee of the People’s Hospital of Xinjiang Uygur Autonomous Region. Written informed consent was obtained from all patients before study commencement.

Diagnosis criteria

Hypertension is defined as SBP ≥ 140 mmHg and/or DBP ≥ 90 mmHg on 3 different days, or the current usage of any antihypertensive medication. OSA is defined as AHI (apnea-hypopnea index) ≥ 5 based on the in-laboratory polysomnography. Diabetes is defined as fasting glucose ≥ 7.0 mmol/L, the usage of glucose-lowering medication, or self-reported history of diabetes.

Follow-up and Outcomes

All patients were followed up and collected all clinical outcomes via outpatient visits, inpatient medical records, or telephone calls by the trained nurses and physicians. The deadline for follow-up was Jan 2021. The BP was measured at least 3 times on different days during follow-up, and the treatment of OSA after the initial diagnosis was recorded. For patients who suffered major adverse cardiovascular and cerebrovascular events (MACCEs), the levels of BP before MACCEs were collected via medical records. For each patient, the follow-up time was from the baseline diagnostic PSG to the first confirmed (adjudicated) event of the newly-diagnosed MACCEs. The primary outcomes were the MACCEs during the study period. Fatal MACCEs were deaths from CVDs. Non-fatal MACCEs included myocardial infarction (MI), non-fatal stroke (including TIA), revascularization (percutaneous coronary intervention and coronary artery bypass grafting), and cardiac rehospitalization because of unstable angina or heart failure. All endpoints were defined in accordance with the proposed definitions by the Standardized Data Collection for Cardiovascular Trials Initiative^[10]. If MACCE was diagnosed beyond our hospital, the patients were asked to provide the diagnosis and treatment data. For the sudden death cases, the cause of death was asked from bereaved relatives and verified by the hospital death certificate or hospitalization data, or the local police system. All the clinical events were confirmed by medical documents and identified by the clinical event committee of our hospital. The international classification of diseases (ICD-10) classification code was used to classify cases of a deadly disease. Further, we defined cardiac events as the fatal and non-fatal heart-related MACCEs, and cerebrovascular events as the fatal and non-fatal stroke (TIA included). CPAP use was recorded. Regular use was defined as average use ≥ 4 hours/night for > 70% of the follow-up period. The others with no or less than regular use were thought as ‘untreated’. Finally, 3267 patients with full follow-up information were included for analysis in this study (Fig. 1).

UROSAH: Urumqi Research on Sleep Apnea and Hypertension; OSA:obstructive sleep apnea; CVDs: cardiovascular diseases.

Statistical analysis

Continuous variables were reported as mean ± standard deviation (SD) if normally distributed and as the median and interquartile range (IQR) if not. Differences between the two groups for normally distributed continuous variables were compared using the independent samples t-test and the Mann Whitney U test was used for non-normally distributed continuous variables. Categorical variables were presented as observed numbers and percentages and compared using the Pearson Chi-square test among groups. The cumulative incidence of primary outcomes was estimated by Kaplan-Meier survival curves, and the log-rank test was used to estimate the difference between the different levels of BP control. Cox proportional hazards models were performed to test the association between CVDs outcomes (including MACCEs, cardiac events, and cerebrovascular events) and the levels of BP control in the total cohort and patients with OSA. The risk factors such as age, sex, body mass index, baseline systolic blood pressure and diastolic blood pressure, apnea hyponea index, low-density lipoprotein cholesterol, eGFR, smoking, type 2 diabetes, and the usage of drugs were adjusted. Furthermore, to eliminate the impact of OSA-specific treatment on the association between BP control and MACCEs, we conducted the sensitivity analysis in the OSA population by excluding individuals who use CPAP regularly. Data were analyzed using SPSS statistical software (version 25.0, SPSS Inc., Chicago, Illinois). All analyses were two-tailed and a P value of < 0.05 was statistically significant.

Baseline characteristics of the participants

A total of 3267 patients (2138 males and 1129 females) were included and divided into 3 groups by the follow-up blood pressure. Table 1 showed the baseline characteristics of the total cohort and the participants among 3 groups. The mean age was 48.6 years and 77.6% patients were diagnosed as OSA at baseline. 379 out of 3267 hypertensives experienced MACCE during a median follow-up of 7.0 years.

Table 1

Baseline characteristics of the participants
	Total cohort (n = 3267)	≥ 140/90mmHg (n = 1789)	120–140/80-90mmHg (n = 993)	≤ 120/80mmHg (n = 485)	P value
Baseline anthropometric indices
Age (yr)	48.6 ± 10.9	47.9 ± 10.9	49.3 ± 10.8	49.4 ± 11.0	0.002
Gender (Male,%)	2138(65.4)	1198(67.0)	649(65.4)	291(60.0)	0.017
BMI (kg/m²)	28.0 ± 3.8	28.3 ± 3.9	27.8 ± 3.6	27.2 ± 3.7	< 0.001
Baseline office SBP (mmHg)	139.6 ± 19.5	142.5 ± 19.7	136.9 ± 18.9	134.7 ± 18.2	< 0.001
Baseline office DBP (mmHg)	91.7 ± 13.9	93.7 ± 13.8	90.0 ± 13.9	88.2 ± 12.8	< 0.001
Smoker (n,%)	1071(32.8)	620(34.7)	317(31.9)	134(27.6)	0.011
Baseline biochemical tests
GGT (mmol/L)	28.4 ± 22.2	29.0 ± 24.3	27.1 ± 19.1	28.8 ± 20.1	0.109
GOT (mmol/L)	22.2 ± 14.2	22.5 ± 17.0	21.4 ± 9.4	22.5 ± 10.1	0.119
eGFR (ml/min/1.73m²)	96.9 ± 21.8	97.5 ± 22.1	97.1 ± 21.6	94.6 ± 21.3	0.031
LDL-c (mmol/L)	2.6 ± 0.8	2.6 ± 0.8	2.6 ± 0.8	2.5 ± 0.8	0.068
Baseline PSG parameters
Total sleep time (mins)	390.3 ± 51.8	390.6 ± 52.5	391.5 ± 52.7	386.7 ± 47.1	0.297
Sleep efficiency (%)	73.5 ± 9.6	73.6 ± 9.8	73.6 ± 9.3	72.8 ± 9.6	0.335
AHI (event/h)	14.2(5.6–26.8)	14.9(5.9–27.9)	18.5 ± 17.9	18.1 ± 17.8	0.003
Mean SaO₂ (%)	92.4 ± 2.7	92.3 ± 2.7	92.4 ± 2.8	92.5 ± 2.5	0.241
Nadir SaO₂ (%)	80.7 ± 7.6	80.3 ± 7.7	80.9 ± 7.7	81.7 ± 6.9	0.001
CHD (n,%)	361(11.0)	203(11.3)	106(10.7)	52(10.7)	0.837
Diabetes (n,%)	540(16.5)	307(17.2)	151(15.2)	82(16.9)	0.401
OSA (n,%)	2536(77.6)	1416(79.2)	756(76.1)	364(75.1)	0.063
Mild OSA (n,%)	967(29.6)	529(29.6)	304(30.6)	134(27.6)
Moderate OSA (n,%)	811(24.8)	456(25.5)	223(22.5)	132(27.2)
Severe OSA (n,%)	758(23.2)	431(24.1)	229(23.1)	98(20.2)	0.076
Antihypertensive regimen (n,%)
0–1 drug	1160(35.5)	532(29.7)	421(42.4)	207(42.7)	< 0.001
2 drugs combination	1635(50.0)	959(53.6)	451(45.7)	222(45.8)
≥3 drugs combination	472(14.4)	298(16.7)	118(11.9)	56(11.5)
Lipid-modifying agents (n,%)	2030(62.1)	1135(63.4)	607(61.1)	288(59.4)	0.193
Antiplatelet drugs (n,%)	1601(49.0)	862(48.2)	493(49.6)	246(50.7)	0.544
Antidiabetic drugs use (n,%)	479(14.7)	262(14.6)	140(14.1)	77(15.9)	0.662
Follow-up mean SBP (mmHg)	136.7 ± 16.9	146.7 ± 15.8	129.3 ± 5.3	116.0 ± 5.9	< 0.001
Follow-up mean DBP (mmHg)	86.3 ± 12.1	92.9 ± 11.3	80.1 ± 6.2	74.5 ± 6.8	< 0.001
Follow-up, median (IQR),y	7.0(6.0-8.1)	7.0(6.1-8.0)	7.0(6.1–8.1)	6.9(5.8-8.0)	0.221
Person-years followed,y	22017.5	11894.0	6641.7	3097.3
Total number of MACCEs (n)	379	225	99	55
Outcome per 1000 person-years	17.2	18.9	14.9	17.7

BMI: body mass index, SBP: systolic blood pressure, DBP: diastolic blood pressure, GGT:Alanine transaminase, GOT: Aspartate transaminase, eGFR: glomerular filtration rate, LDL-C: low-density lipoprotein cholesterol, AHI: apnea hyponea index, SaO₂:saturation, CHD: coronary heart diseases; OSA: obstructive sleep apnea; Mean level of follow-up BP were calculated in 3267 patients.

MACCE incidence

Figure 2 illustrated the crude incidence of MACCEs, cardiac events, and cerebrovascular events in different groups of BP control. The incidence of stroke decreased significantly when BP was not controlled < 140/90mmHg (log-rank test, P = 0.022, Fig. 2B). But no significant difference was observed between BP control and MACCEs and cardiac events (Fig. 2A, 2C).

BP control and the incident MACCEs in the total cohort

Table 2 presented the association between BP control and the incident MACCEs, cerebrovascular events, and cardiac events in the total cohort. After full risk adjustment, BP control of 120–140/80-90mmHg was associated with the lowest risk of cerebrovascular events only(HR: 0.53, 95%CI: 0.35–0.82). Separately, the SBP control of 120-140mmHg was associated with the lowest HR of the incident MACCEs and cerebrovascular events. Compared to patients with DBP ≥ 90mmHg, patients with BP controlled lower than 80mmHg had a reduced risk of cerebrovascular events by approximately 50% [(HR:0.51, 95%CI: 0.29–0.88)]. However, no benefits of SBP control and DBP control for cardiac events were observed.

Table 2

The association of blood pressure control and MACCEs, cerebrovascular events and cardiac events in total cohort (n = 3267)
Total cohort	MACCEs (n = 379)		cerebrovascular events (n = 138)		Cardiac events (n = 220)
BP control (mmHg)	HR(95%CI)	P value	HR(95%CI)	P value	HR(95%CI)	P value
≥ 140/90	1.0		1.0		1.0
120–140/80–90	0.83(0.65–1.06)	0.129	0.53(0.35–0.82)	0.004	1.03(0.76–1.40)	0.860
≤ 120/80	1.10(0.81–1.48)	0.552	0.69(0.40–1.20)	0.192	1.31(0.88–1.93)	0.183
SBP control (mmHg)	HR(95%CI)	P value	HR(95%CI)	P value	HR(95%CI)	P value
≥ 140	1.0		1.0		1.0
120–140	0.73(0.58–0.91)	0.006	0.46(0.31–0.69)	< 0.001	0.93(0.69–1.25)	0.624
≤ 120	0.90(0.67–1.21)	0.480	0.58(0.34–0.97)	0.039	1.09(0.74–1.60)	0.660
DBP control (mmHg)	HR(95%CI)	P value	HR(95%CI)	P value	HR(95%CI)	P value
DBP ≥ 90	1.0		1.0		1.0
85 ≤ DBP < 90	0.71(0.51–0.98)	0.040	0.72(0.43–1.20)	0.210	0.81(0.55–1.18)	0.270
80 ≤ DBP < 85	0.84(0.64–1.09)	0.185	0.69(0.44–1.07)	0.100	0.93(0.66–1.31)	0.689
DBP < 80	0.71(0.53–0.96)	0.026	0.51(0.29–0.88)	0.016	0.71(0.46–1.10)	0.123

*HR: hazard ratio, BP: blood pressure. Adjusted for age, sex, body mass index, baseline systolic blood pressure and diastolic blood pressure, apnea hyponea index, low-density lipoprotein cholesterol, eGFR, smoking, type 2 diabetes, lipid-lowering drugs, antidiabetic drugs and antiplatelet drugs.

BP control and the incident MACCEs in patients with and without OSA

As to patients with OSA, compared with the subjects with SBP ≥ 140mmHg, the risk of cerebrovascular events was significantly reduced in patients with BP control < 140mmHg, and the HR was very similar in the 120-140mmHg and < 120mmHg groups. Taking DBP > 90mmHg as a reference, the risk of MACCEs decreased by 31% when DBP < 80mmHg, while the risk of cerebrovascular events could decrease by 54%. However, it had not yet been observed that a decrease in BP can bring significant benefits from cardiac events. In the non OSA population, we observed a decrease in the risk of MACCEs and stroke after SBP control < 140mmHg or DBP control < 90mmHg, although there was no statistically significant difference (Table 3).

Table 3

The association between blood pressure control and incident MACCEs, cerebrovascular events, and cardiac events in hypertensives with and without OSA
	Patients with OSA			Patients without OSA
	MACCEs (n = 318)	cerebrovascular events (n = 106)	Cardiac events (n = 194)	MACCEs (n = 61)	cerebrovascular events (n = 32)	Cardiac events (n = 26)
BP control (mmHg)	HR(95%CI)	HR(95%CI)	HR(95%CI)	HR(95%CI)	HR(95%CI)	HR(95%CI)
≥ 140/90	1.0	1.0	1.0	1.0	1.0	1.0
120–140/80–90	0.89(0.69–1.15)	0.55(0.34–0.90)	1.07(0.77–1.47)	0.59(0.31–1.14)	0.49(0.19–1.24)	0.81(0.30–2.16)
≤ 120/80	0.99(0.71–1.41)	0.60(0.31–1.17)	1.18(0.77–1.82)	1.58(0.81–3.07)	1.02(0.37–2.84)	1.95(0.71–5.36)
SBP control (mmHg)
≥ 140	1.0	1.0	1.0	1.0	1.0	1.0
120–140	0.78(0.61–0.99)	0.52(0.34–0.82)	0.93(0.68–1.27)	0.49(0.26–0.93)	0.28(0.11–0.73)	1.00(0.37–2.70)
≤ 120	0.83(0.60–1.16)	0.53(0.28–0.98)	0.99(0.66–1.52)	1.20(0.62–2.35)	0.73(0.28–1.92)	1.78(0.60–5.33)
DBP control (mmHg)
DBP ≥ 90	1.0	1.0	1.0	1.0	1.0	1.0
85 ≤ DBP < 90	0.76(0.53–1.07)	0.71(0.40–1.27)	0.79(0.50–1.24)	0.50(0.19–1.31)	0.77(0.25–2.38)	0.23(0.03–1.81)
80 ≤ DBP < 85	0.83(0.62–1.11)	0.66(0.40–1.11)	0.90(0.62–1.31)	0.96(0.51–1.82)	0.81(0.33–2.02)	1.18(0.47–2.99)
DBP < 80	0.71(0.51–0.99)	0.46(0.25–0.88)	0.84(0.56–1.27)	0.73(0.33–1.58)	0.71(0.23–2.22)	0.56(0.17–1.91)

*HR: hazard ratio. BP:blood pressure, OSA: obstructive sleep apnea. Adjusted for age, sex, body mass index, baseline systolic blood pressure and diastolic blood pressure, low-density lipoprotein cholesterol, eGFR, apnea hyponea index, smoking, type 2 diabetes, lipid-lowering drugs, antidiabetic drugs and antiplatelet drugs.

Sensitivity analysis

To clarify the effect of drug-induced BP control on MACCEs in patients with OSA, the sensitivity analysis was conducted by excluding 114 individuals who received regular CPAP treatment. Similar to the results in the total cohort, OSA patients with DBP < 80mmHg had a decrease in MACCEs of about 30% [HR (95% CI): 0.71 (0.51–1.98), P = 0.040], and a decrease in the risk of stroke of 58% [HR (95% CI): 0.42 (0.22–0.82), P = 0.011] taking DBP control ≥ 90mmHg as a reference, but no benefit from BP control was found for cardiac events, and BP ≤ 120/80mmHg seemed to increase the risk of cardiac events (Table 4).

Table 4

Sensitivity analysis of the effect of blood pressure control on MACCEs, cerebrovascular and cardiac events in OSA patients without CPAP treatment (n = 2422)
	MACCEs (n = 303)		cerebrovascular events (n = 100)		Cardiac events (n = 185)
BP control(mmHg)	HR(95%CI)	P value	HR(95%CI)	P value	HR(95%CI)	P value
≥ 140/90	1.0		1.0		1.0
120–140/80–90	0.85(0.65–1.11)	0.241	0.55(0.33 − 0.09)	0.018	1.01(0.72–1.40)	0.978
≤ 120/80	0.99(0.69–1.41)	0.939	0.50(0.24–1.05)	0.067	1.23(0.80–1.90)	0.345
Systolic BP(mmHg)	HR(95%CI)	P value	HR(95%CI)	P value	HR(95%CI)	P value
≥ 140	1.0		1.0		1.0
120–140	0.78(0.60-1.00)	0.052	0.54(0.34–0.85)	0.008	0.91(0.66–1.26)	0.559
≤ 120	0.85(0.60–1.19)	0.339	0.47(0.24–0.92)	0.028	1.06(0.69–1.61)	0.802
Diastolic BP(mmHg)	HR(95%CI)	P value	HR(95%CI)	P value	HR(95%CI)	P value
DBP ≥ 90	1.0		1.0		1.0
85 ≤ DBP < 90	0.75(0.53–1.07)	0.112	0.72(0.40–1.28)	0.258	0.78(0.45–1.24)	0.289
80 ≤ DBP < 85	0.76(0.56–1.03)	0.080	0.57(0.33–0.99)	0.046	0.85(0.58–1.25)	0.403
DBP < 80	0.71(0.51–1.98)	0.040	0.42(0.22–0.82)	0.011	0.86(0.57–1.31)	0.490

*HR:hazard ratio. BP: blood pressure. 114 patients who received regular use of continuous positive airway pressure (CPAP) were excluded. Adjusted for age, sex, body mass index, baseline systolic blood pressure and diastolic blood pressure, low-density lipoprotein cholesterol, eGFR, apnea hyponea index, smoking, type 2 diabetes, lipid-lowering drugs, antidiabetic drugs and antiplatelet drugs.

In the previous study(UROSAH study), we showed the nonlinear relationship between Chinese visceral adiposity index and new-onset myocardial infarction in patients with hypertension and obstructive sleep apnoea^[9], However, the goal of blood pressure control in this population is currently unclear. Hence, we tried to explore the potential blood pressure goal of cardiovascular benefit in this special population by observing the correlation between blood pressure control level and MACCEs, so as to provide a reference for the prevention and treatment of cardiovascular disease in this population. In the present study, we observed antihypertensive-drug-induced BP control at 120–140/80-90mmHg showed possible beneficial effect on incident MACCEs in the total cohort after adjustment for risk confounders. Further, SBP ≤ 120mmHg and DBP < 80mmHg showed more cerebrovascular benefits in patients with hypertension and OSA. Our study may provide more novel information for BP management of hypertension and OSA.

2020 International Society of Hypertension(ISH) global hypertension practice guidelines suggested BP < 140/90mmHg as the essential target of office BP for treated hypertension and < 130/80mmHg as the optimal target for treated hypertensives aged < 65yrs^[7], a lower target BP was strongly recommended also in some high CVDs risk groups ^[11]. However, as a high CVDs risk group, the target of BP control for hypertension with OSA is unclear so far. In this study, when the systolic BP and diastolic BP were considered simultaneously, the lowest HRs of MACCEs, cerebrovascular disease and cardiovascular events were observed when BP was at 120–140/80-90mmHg compared to patients with uncontrolled hypertension both in the total cohort and in patients with OSA group, although no significant association was found. Moreover, the risk of cardiac events appeared to be increasing when the BP control ≤ 120/80mmHg, which was not consistent with the guidelines. The pathophysiology of OSA could be considered to explain the results, such as OSA-caused nocturnal intermittent hypoxia, hypercoagulable state, et al. Hence, it is speculated that untreated OSA may require slightly higher perfusion pressure to ensure blood and oxygen supply to coronary and cerebral vessels. In the present study, the following BP levels were based on the means of the BP measurements before MACCEs, which would make the results more reliable and tend to underestimate the risk of the events. However, due to a retrospective cohort study, our findings provided preliminary reference of the BP control for hypertension with OSA, especially for middle-aged hypertensives, who were thought to be a particularly important group in light of their uniquely elevated risk of CVDs morbidity and mortality^[12].

When the systolic BP and diastolic BP control were considered separately, it was found that when SBP was controlled at 120–140 mmHg, the risks of MACCEs and cerebrovascular events in OSA patients with hypertension were reduced significantly. With the decrease of DBP, the risk of MACCEs and cerebrovascular events significantly decreased, especially when the DBP < 80mmHg, the risk of stroke can be reduced by about 50%. Similar to the results of ALLHAT study^[13], our findings also supported that the risk pattern of SBP and DBP may differ by clinical outcomes in hypertension with OSA. As Franz Messerli wrote in his editorial, "the lower the better" is correct for stroke prevention. If there was no risk to the heart, the SBP with the best brain protection is 110–120 mmHg^[14]. As well, the latest study found that intensive SBP control (SBP < 120mmHg) was associated with increased cerebral perfusion, most notably in participants with a history of CVDs^[15]. However, the role of DBP in the prediction of CVDs is inconsistent. In 2017, the ACC/AHA hypertension-management guidelines did not consider DBP in the determination of cardiovascular risk ^[16]. But a very recent study pointed out that systolic and diastolic hypertension independently predicted adverse outcomes, no matter which threshold defines hypertension^[17]. Our findings indicated that DBP would be an important risk factor for stroke in hypertensives with OSA. Some reasons could be discussed: (1) physiologically, the brain can maintain relatively constant blood flow in case of large fluctuations in perfusion pressure by automatic regulation. However, unlike the brain, cardiac perfusion mainly occurs in diastole. Therefore, very low DBP will easily affect myocardial perfusion rather than brain perfusion. (2)The possible mechanisms for the substrate and trigger of cardiac events in patients with OSA include inflammation/ atherosclerosis, endothelial dysfunction, hypercoagulability, left atrial enlargement, sympathetic activation^[18], and excessive mechanical stress on the heart and large artery walls caused by strong intrathoracic pressure changes^[6]; (3)In addition, OSA could also lead to plaque instability, plaque vulnerability and coronary artery calcification^[19], which may affect vasodilation function of the artery. (4) It is well-known that effective antihypertensive therapy is vital to prevent CVDs for adults with hypertension. All subjects in our study were prescribed individualized antihypertensive regimens after systemic evaluation of hypertension, and if necessary, lipid-lowering drugs, antidiabetic drugs and/or antiplatelet drugs were also used, which may attenuate the association between BP control and incident risk of MACCE. Moreover, as the most recent prospective cohort study named Diastolic Chronic Heart Failure Study (DIAST-CHF) explained, OSA did not show a significant adverse effect on cardiovascular morbidity and mortality in patients with cardiovascular risk factors ^[20], in which the effective pharmacological interventions and the limited number of severe OSA may be the possible reasons.

There are several limitations. Firstly, because the cardiovascular cause of death counted for 54.7% (41/75) of all-cause death, the association between BP control and the specific cause of death was not analyzed. Alternatively, the cases of the cardiovascular cause of death were respectively included in the MACCEs, cerebrovascular and cardiac events for analysis. Secondly, as complained in many studies ^[21], a substantial proportion of patients refused OSA-specific treatment although all severe OSA patients were initially recommended CPAP treatment as soon as they were diagnosed, nonetheless, these patients were taken antihypertensive drugs and followed up in our hypertension center, they provided information of the natural history of untreated OSA in hypertension. Thirdly, as a retrospective study, we did not use the models to adjust the role of variables over time (e.g. changes in complications). Fourthly, because a large number of individuals with OSA were untreated, we did not explore the BP control and the risk of MACCEs via comparing hypertensive OSA patients with and without treatment with CPAP. Though continuous positive airway pressure (CPAP) is known as an effective treatment for OSA, OSA is often undertreated in cardiovascular practice^[3]. The SAVE trial even concluded that the use of CPAP did not prevent CVDs in patients with moderate-to-severe OSA and established CVDs^[22]. The effects of CPAP treatment on blood pressure and long-term cardiovascular outcomes in patients with hypertension and OSA still need to be further explored. Finally, as a retrospective cohort study, our research proposes considerations for BP control goals rather than estimates the BP goals of hypertensive coexists with OSA by analyzing the correlation between BP control levels and long-term CVDs outcomes, the results need the prospective studies to verify.

In this retrospective study, antihypertensive-drug-induced BP control at 120–140/80-90mmHg showed possible beneficial effect on incident MACCEs. However, SBP ≤ 120mmHg or DBP < 80mmHg respectively showed the significant benefit to reduce incident cerebrovascular events in hypertensives with OSA.

Ethics approval and consent to participate:

This study was conducted according to the Declaration of Helsinki and approved by the Ethics Committee of the People’s Hospital of Xinjiang Uygur Autonomous Region(No.2019030662). Written informed consent was obtained from all patients before study commencement.

Consent for publication

Not applicable.

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.

Competing interests

The authors declare that they have no conflicts of interest.

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).

Authors’ Contributions

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.

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.

Tietjens JR, Claman D, Kezirian EJ, De Marco T, Mirzayan A, Sadroonri B, Goldberg AN, Long C, Gerstenfeld EP, Yeghiazarians Y. Obstructive sleep apnea in cardiovascular disease: a review of the literature and proposed multidisciplinary clinical management strategy. J Am Heart Assoc. 2019;8:e010440. 10.1161/JAHA.118.010440.
Fava C, Dorigoni S, Dalle Vedove F, Danese E, Montagnana M, Guidi GC, Narkiewicz K, Minuz P. Effect of CPAP on blood pressure in patients with OSA/hypopnea: a systematic review and meta-analysis. Chest. 2014;145:762–71. 10.1378/chest.13-1115.
Yeghiazarians Y, Jneid H, Tietjens JR, Redline S, Brown DL, El-Sherif N, Mehra R, Bozkurt B, Ndumele CE, Somers VK. Obstructive Sleep Apnea and Cardiovascular Disease: A Scientific Statement From the American Heart Association. Circulation. 2021;144:e56–e67. 10.1161/CIR.0000000000000988.
Benjafield AV, Ayas NT, Eastwood PR, Heinzer R, Ip MSM, Morrell MJ, Nunez CM, Patel SR, Penzel T, Pépin JL, Peppard PE, Sinha S, Tufik S, Valentine K, Malhotra A. Estimation of the global prevalence and burden of obstructive sleep apnoea: a literature-based analysis. Lancet Respir Med. 2019;7:687–98.
Zolotoff C, Bertoletti L, Gozal D, Mismetti V, Flandrin P, Roche F, Perek N. Obstructive Sleep Apnea, Hypercoagulability, and the Blood-Brain Barrier. J Clin Med. 2021; 10: (14), undefined. DOI:10.3390/jcm10143099.
Malcolm K, John S. Mechanisms of vascular damage in obstructive sleep apnea. Nat Rev Cardiol. 2010;7:677–85.
Unger T, Borghi C, Charchar F, Khan NA, Poulter NR, Prabhakaran D, Ramirez A, Schlaich M, Stergiou GS, Tomaszewski M, Wainford RD, Williams B, Schutte AE. 2020 International Society of Hypertension Global Hypertension Practice Guidelines. Hypertension. 2020;75:1334–57.
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;182:954–60. 10.1164/rccm.200912-1803OC.
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 apnoea: insights from a cohort study. J Inflamm Res. 2022;15:687–700.
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. DOI: 10.1016/j.jacc.2014.12.018.
Al-Makki A, DiPette D, Whelton PK, Murad MH, Mustafa RA, Acharya S, Beheiry HM, Champagne B, Connell K, Cooney MT, Ezeigwe N, Gaziano TA, Gidio A, Lopez-Jaramillo P, Khan UI, Kumarapeli V, Moran AE, Silwimba MM, Rayner B, Sukonthasan A, Yu J, Saraffzadegan N, Reddy KS, Khan T. Hypertension Pharmacological Treatment in Adults. Volume 79. A World Health Organization Guideline Executive Summary.Hypertension; 2022. pp. 293–301.
Bonsignore MR, Baiamonte P, Mazzuca E, Castrogiovanni A, Marrone O. Obstructive sleep apnea and comorbidities: A dangerous liaison. Multidiscip Respir Med. 2019;14:8.
Itoga NK, Tawfik DS, Montez-Rath ME, Chang TI. Contributions of systolic and diastolic blood pressures to cardiovascular outcomes in the ALLHAT study. J Am Coll Cardiol. 2021;78:1671–8.
Franz HM, Evgeniya VS, Emrush R. Optimal BP targets to prevent stroke and MI: is there a lesser of 2 evils? JACC. 2021,78(17): 1679–81. DOI: 10.1016/j.jacc.2021.09.013.
Dolui S, Detre JA, Gaussoin SA, Herrick JS, Wang DJJ, Tamura MK, Cho ME, Haley WE, Launer LJ, Punzi HA, Rastogi A, Still CH, Weiner DE, Wright JT, Williamson JD, Wright CB, Bryan RN, Bress AP, Pajewski NM, Nasrallah IM. Association of Intensive vs Standard Blood Pressure Control With Cerebral Blood Flow: Secondary Analysis of the SPRINT MIND Randomized Clinical Trial. JAMA Neurol. 2022;79:380–9.
Whelton PK, Carey RM, Aronow WS, Casey DE, Collins KJ, Dennison Himmelfarb C, DePalma SM, Gidding S, Jamerson KA, Jones DW, MacLaughlin EJ, Muntner P, Ovbiagele B, Smith SC, Spencer CC, Stafford RS, Taler SJ, Thomas RJ, Williams KA, Williamson JD, Wright JT, 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH. prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71(6):e13–15. /ASPC/NMA/PCNA guideline for the.
Flint AC, Conell C, Ren X, Banki NM, Chan SL, Rao VA, Melles RB, Bhatt DL. Effect of systolic and diastolic blood pressure on cardiovascular outcomes.N Engl. J Med. 2019;381:243–51.
Mooe T, Franklin KA, Wiklund U, Rabben T, Holmström K. Sleep-disordered breathing and myocardial ischemia in patients with coronary artery disease. Chest. 2000;117:1597–602.
Shah NA, Yaggi HK, Concato J, Mohsenin V. Obstructive sleep apnea as a risk factor for coronary events or cardiovascular death. Sleep Breath. 2010;14:131–6.
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;154:127–32.
Liao WJ, Song LJ, Yi HL, Guan J, Zou JY, Xu HJ, Wang G, Ma F, Zhou LB, Chen YQ, Yan LB, Deng ZC, McNicholas WT, Yin SK, Zhong NS, Zhang XW. Treatment choice by patients with obstructive sleep apnea: data from two centers in China. J Thorac Dis. 2018;10:1941–50.
McEvoy RD, Antic NA, Heeley E, Luo Y, Ou Q, Zhang X, Mediano O, Chen R, Drager LF, Liu Z, Chen G, Du B, McArdle N, Mukherjee S, Tripathi M, Billot L, Li Q, Lorenzi-Filho G, Barbe F, Redline S, Wang J, Arima H, Neal B, White DP, Grunstein RR, Zhong N, Anderson CS, SAVE Investigators and Coordinators. CPAP for prevention of cardiovascular events in obstructive sleep apnea. N Engl J Med. 2016;375:919–31. 10.1056/NEJMoa1606599.

No competing interests reported.

Download PDF

Journal Publication

published 21 Nov, 2023

Read the published version in BMC Cardiovascular Disorders →

Editorial decision: Major revision
31 Aug, 2023
Reviewers agreed at journal
26 Aug, 2023
Reviews received at journal
30 Jul, 2023
Reviewers agreed at journal
25 Jul, 2023
Reviewers invited by journal
20 Jul, 2023
Editor assigned by journal
17 Jul, 2023
Editor invited by journal
11 Jul, 2023
Submission checks completed at journal
11 Jul, 2023
First submitted to journal
27 Jun, 2023

You are reading this latest preprint version

The association between blood pressure control and long-term cardiovascular outcomes in hypertension coexists with obstructive sleep apnea

Status:

Journal Publication

Version 1

Abstract

Figures

Introduction

Material and methods

Study design and subjects

Diagnosis criteria

Follow-up and Outcomes

Statistical analysis

Results

Baseline characteristics of the participants

MACCE incidence

BP control and the incident MACCEs in the total cohort

BP control and the incident MACCEs in patients with and without OSA

Sensitivity analysis

Discussion

Conclusion

Declarations

References

Additional Declarations

Status:

Journal Publication

Version 1