Obstructive sleep apnea and hypertension – epidemiological, diagnostical and treatment aspects

Abstract

ABSTRACT Background: Obstructive sleep apnea (OSA) and hypertension are two common disorders both strongly connected with the development of future atrial fibrillation, and major adverse cardiovascular events (MACE), such as stroke, myocardial infarction, cardiac failure and premature cardiovascular (CV) death. As both conditions share several common risk factors and OSA promotes the development of hypertension, patients often have both conditions. Early studies suggest OSA patients have a higher risk of developing these CV events. It is known that blood pressure control is poor in patients with OSA and they are harder to treat successfully with anti-hypertensive treatment (AHT). This implies that even when patients are correctly diagnosed with both disorders (which is often not the case), adequate treatment may still not be achieved, resulting in a persistently elevated risk of MACE. To optimize management and reduce long-term risk, further information is needed to determine which patients are most likely to develop CV events and whether specific classes of AHT are particularly suitable for these individuals.

Included studies and investigated questions: In this thesis a novel method to predict vascular function in suspected OSA patients, was addressed in study I. Pulse Propagation Time (PPT) as a marker of arterial stiffness measured during sleep, was studied in OSA with and without hypertension. We hypothesized that PPT information collected during routine sleep investigations may improve our ability to identify patients with high CV risk. We described for the first time the changes in PPT during different sleep stages, and vascular stiffness was consistently higher in patients with OSA and hypertension than controls without these disorders. In study II, we assessed the incidence of MACE in patients with OSA and/or hypertension. We compared groups with hypertension, OSA or both disorders against normotensive controls (155,830 subjects in total). With a median follow-up time of 6.8 years, we used COX regression models to compare hazard ratios/risks for the groups, with first MACE or death as main outcomes. We adjusted for confounding factors and investigated modifying factors like adherence to therapies in the models. In addition, the protective effects of PAP treatment were assessed. In the adjusted model, MACE risk was highest in patients with both OSA and hypertension with HR 7.0 (6.2-7.9), followed by hypertensive controls with 3.2 (2.9-3.7) and patients with OSA alone, HR 2.6 (2.2-3.0) compared to normotensive controls. All-cause mortality had a similar pattern but lower HRs of 3.1 (2.8-3.5), 2.2 (2.0-2.4) and 1.6 (1.4-1.8) respectively. OSA patients experience their first MACE earlier in life than hypertension status matched controls—on average 5 years earlier if normotensive and 1.6 years earlier if hypertensive. Positive airway treatment (PAP) treatment of OSA, reduces the MACE risk in a dose-response manner. PAP adherence reduced risk with 22-39% from 2-<4 to 8 hours or more per night. In study III we studied AHT in 5,818 hypertensive patients diagnosed with OSA. Analyses were performed in a large pan-European database (ESADA) to investigate OSA patients with hypertension before the start of PAP treatment, identifying differences in office blood pressure (BP) control depending on what AHT class (betablocker, calcium channel blocker, diuretic, renin-angiotensin blocker (RAB) or centrally acting antihypertensives) or combination used. BP was uncontrolled in 66% of the population. There were significant differences, 2-5 mmHg in BP between AHT groups, favouring betablocker treatment compared to other AHT classes. In study IV, we studied changes in BP control in 1,935 hypertensive OSA patients from ESADA, following PAP treatment stratified by antihypertensive drug class or combination. Overall, the proportion of patients with well controlled hypertension increased by 10-15% with PAP treatment. Further improvement of BP and more favourable BP control were achieved with RAB. Mean BP improvement was 3-4 mmHg with PAP and patients with combinations including RAB had a BP reduction of 4.8-6.9 mmHg. Conclusions: Oximetry based beat-by-beat contour pulse wave analysis was used to assess overnight vascular stiffness (PPT) and has sleep stage specific changes. Slow wave sleep (N3, deep sleep) had the lowest vascular stiffness. PPT also decreases with higher OSA severity and in hypertension as a marker of increasing vascular stillness. PPT may be a valuable tool to better monitor vascular ageing and predict increased CV risk, during regular sleep studies. Patients with hypertension and OSA have markedly increased risk for earlier MACE/all-cause death than controls and even compared to patients with OSA or hypertension alone and OSA patients get their first CV event earlier in life. PAP treatment mitigated the risk in a dose-response manner with increasing PAP adherence. AHT in hypertensive OSA patients are less likely to reach intended BP control compared to non-OSA populations. Adequate OSA control improves BP control but assessment of BP status during PAP treatment is recommended as modification and/or escalation of AHTs may improve BP control. Well-treated OSA patients seem to be more suitable for RAB while untreated OSA patients had better results from betablockers alone or in combination with diuretics. This highlights the need to consider AHT when initiating OSA treatment.