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Hypertension is one of the key risk factors for cardiovascular disease.[[1,2]] In New Zealand Māori have the highest level of risk for hypertension of all ethnic groups.[[3]] Although the first line of treatment for hypertension is medication, blood pressure (BP) is controlled by medications alone in only a fraction of patients.[[4]] Resistant hypertension (RHT) is a subset of hypertension, defined in the Scientific Statement of the American Heart Association[[4]] as “BP remaining above the goal BP in spite of concurrent use of three or more antihypertensive agents, including a diuretic.”[[4]] Currently RHT is recognised as an increasingly common clinical problem, and higher fatal event rates have been identified in RHT compared to hypertension.[[5]] Ambulatory BP over 24h (24h ABP) is recommended to exclude the “white coat/pseudo” (higher clinic BP and normal day-to-day BP), or to “mask” (normal clinic BP and higher day-to-day BP) effects and diagnose RHT, which can be termed as “true RHT” (tRHT).[[6]] RHT diagnosed but not excluding white coat/pseudo or masked hypertension is termed “apparent RHT” (aRHT). Use of country-based, recommended BP diagnostic values and 24h ABP to estimate the prevalence in the relevant population may be important for accessing relevant healthcare and, thereby, to help reduce morbidity and mortality risk.

Based on the BP diagnostic value 140/90 mmHg,[[7]] the estimated global prevalence of aRHT among populations with hypertension is 14.7%, and the estimated prevalence of tRHT is 10.3%.[[8]] On this basis the prevalence of tRHT among the population with aRHT can be calculated as approximately 70%.

Studies that have investigated the prevalence of any type of RHT are limited to Western Pacific (n=4) and Oceania (n=1) geographic regions.[[8]] There are currently no published data on the prevalence of any type of RHT in New Zealand. Māori have a 15% higher use of antihypertensive medication compared to New Zealand Europeans,[[3]] and thus RHT could be high in Māori.

Obstructive sleep apnoea (OSA) and RHT have a close, and strong, bidirectional relationship: each compounds the other.[[4,9]] In New Zealand, as in many other countries, OSA remains under-diagnosed.[[10]] Approximately 70%–80% of adults diagnosed with OSA also have RHT, and 30%–50% with RHT have OSA.[[9]] Thus studies are needed to determine the prevalence of tRHT and its association with OSA in New Zealand.

The aims of this study were, firstly, to explore the prevalence of individuals at high risk of tRHT in a sample population with aRHT, and secondly to describe the characteristics of the study group in order to determine whether a high risk of OSA is associated with individuals at high risk of tRHT in a New Zealand cohort. The outcomes of the study may be beneficial to improve diagnosis, as well as access to healthcare and associated healthcare costs.

Methods

This observational study was registered in the Australia New Zealand Clinical Trial Registry (ACTRN12618001110279p) and ethics approval was obtained from the Health and Disability Ethics Committees, New Zealand Ministry of Health (18/CEN/141).

Study setting and population

The study participants comprised Dunedin-based adults 60 years and younger diagnosed with aRHT.

Inclusion and exclusion criteria

Adults aged 18–60 years diagnosed with primary hypertension and managed pharmacologically with three or more antihypertensive medications, referred to as “aRHT,” were included. Individuals were excluded (not referred by clinicians as potential study participants) if they were diagnosed with acute or chronic kidney disease, had a metabolic disorder such as Cushing’s syndrome, were critically ill or were pregnant.

Sample size

The population was drawn from the Ministry of Health Pharmaceutical Collection Warehouse, via the Best Practice Advocacy Centre (bpac), New Zealand. That database revealed 559 adults in Dunedin under 60 years with hypertension and pharmacologically managed with three or more antihypertensive medications (aRHT). To estimate the prevalence with precision of a 5% margin of error for that finite population size, 228 participants would have been required. A pragmatic decision was made to undertake the study with an adjusted sample size by using an approximated prevalence of 10% and a 10% margin of error. Under these assumptions, the required sample size was estimated to be 35, requiring 70 invitees with an estimated 50% response rate.

Recruitment procedure

The cohort was recruited through general practitioner (GP) referrals and advertising posters. Twenty-five individuals who fulfilled the inclusion criteria consented to participating in the study. After providing informed consent, participants’ demographic data, general health and social habits, self-reported physical activity level, adherence to medications (Morisky Medication Adherence Scale), quality of life (SF-36) and OSA risk (Epworth Sleepiness Scale (ESS) and STOP-BANG questionnaire) were obtained and recorded. The measurements shown in Table 1 were obtained using standardised, calibrated equipment and guidelines.

Outcome measures

The primary outcome, 24h ABP, was recorded using an Ultralite 90217A ABP monitor and 92506 ABP Report Management System (Spacelab Healthcare, WA, USA) in accordance with the instructions in the user manual. The device was fitted to each participant on completion of their questionnaires and anthropometric measurements. The devices were removed at the same time the following day, after recording for 24 hours (day and night). Office/clinic BP was measured at the first visit in accordance with the American Heart Association/American College of Cardiology (AHA/ACC) 2017[[1]] guidelines using an Omron digital BP monitor (HEM 7322, Netherlands).

Secondary outcomes

Scores for ESS and STOP-BANG questionnaires were used to determine levels of excessive daytime sleepiness and risk of OSA. Levels of physical activity and sleep parameters were captured by the ActiGraph GT3XPB, Activitrax monitor (Pensacola, Florida, USA) over a seven-day period in accordance with the instructions in the user manual. The device, an activity monitor fitted on the non-dominant wrist of each participant, was worn continuously for seven days and nights to record their activity and sleep data (Table 1). Each participant completed a six-minute walk test (6MWT) to determine their cardio-respiratory fitness. The short form 36 (SF-36) was administered to determine participants’ quality of life. Collection of anthropometric data (Table 1) followed the protocols documented in the Exercise and Sports Science Australia (ESSA) manual and used standardised calibrated equipment (eg, Seca 876 weighing scale, Seca 217 stadiometer, Seca 201 anthropometric measuring tape) (Table 1).

Statistical analysis

Statistical Package for Social Sciences (SPSS) (IBM SPSS version 25.0 for Windows, NY, USA) was used to analyse the data.[[11]] Characteristics of the sample were reported as means for continuous data and as percentages for categorical data. The proportion with tRHT in the sample population with aRHT was calculated with confidence intervals. Scatterplots were used for BP values and sleep scores to determine the existence of any associations between the variables. The scatterplots did not show a relationship, and thus the correlational analysis was not conducted. Cross-tabulation was used to determine the relationship between tRHT diagnosis and risk of OSA.

Results

Characteristics of the population with RHT

The participants’ mean age was 51.8±8.9 years (range 34–60 years). The majority (n=18: 72%) identified as New Zealand Europeans, two as Māori (8%) and the rest as other ethnicities. On average, the participants had been treated for 5.2±2.2 years for hypertension and the mean number of prescribed medications was 3.2±0.7. The participants showed good adherence (80%) to medication according to the Morisky Medication Adherence Scale.[[12]] The majority (n=16: 64%) of participants were non-smokers. Twenty (80%) were consumers of alcohol (mean number of drinks per week 8.6±12.7) and 18 (72%) were coffee drinkers (mean number of cups 2.5±2.6 per day). Ten participants (40%) used medication for hyperlipidaemia, seven (28%) had diabetes and four (16%) had both conditions. Two had previously had a mild cerebro-vascular accident and one reported a previous history of a myocardial infarction. Means and confidence intervals for BP, anthropometrics, sleep and activity parameters are summarised in Table 2.

Table 1: Blood pressure, sleep and activity parameters of the group. View Table 1.

The mean 24h ABP value of the sample was above the American (AHA/ACC)[[1]] and New Zealand[[2]] diagnostic value for stage II hypertension (>140/90mmHg). The mean daytime sleepiness of the sample was below the cut-off value for excessive daytime sleepiness (ESS score >9)[[13]] in the group, suggesting a lower risk of daytime sleepiness. The objective measurements of sleep showed high mean sleep efficiency (>80%),[[14]] and the mean total sleep time was within the recommended range (7–9h) for an adult.[[15]] Twenty-three participants (92%) reported that they were regularly undertaking exercise or physical activities (mean 4.5±2.2 times per week) within the recommended duration (mean 4.5±2.6 hours per week). The mean moderate to vigorous physical activity (MVPA) duration per week was 12.9% of total time. MVPA per day and step count were above the recommended guidelines (150–300 minutes per week, and over 10,000 steps), although the group reported a higher total sedentary time per week (Table 2). The mean value for Freedson (1998) activity bouts,[[16]] the MVPA with a minimum duration of 10 minutes, was 442.3±386.1 minutes per week, a relatively low value. In contrast, for sedentary bouts, the sedentary time comprising more than 10 minutes[[16]] was reported as 3,226.2±995.0 minutes per week, which is several times higher than Freedson bouts (Table 2).

Overall quality of life for the group was low (SF 36 score 66.7±19.8: 95% CI: 58.6 to 74.9). Particular components of the SF-36-role limitation due to physical health (68.0±40.5), energy/fatigue (53.0±25.4), health change (51.0±26.5) and general health (49.8±20.6) each contributed to the overall low quality of life score for the group.

Prevalence of individuals at high risk of tRHT

The mean office BP values for the group were above 130/80 mmHg, indicating that all the participants (n=25) could be categorised as aRHT.[[1,2,17]] The prevalence of high risk of tRHT among the group with RHT was 88% (95% CI: 68.8 to 97.5). The percentages for the categories of RHT based on the 24h ABP for the group are summarised in Table 2.

Table 2: Approximate prevalence of resistant hypertension categories (diagnosed based on 24h ABP).

nRHT: Non-resistant hypertension, aRHT: Apparent resistant hypertension, tRHT: True resistant hypertension, pRHT: Pseudo resistant hypertension, wcRHt: White coat resistant hypertension.

OSA risk in individuals at high risk of tRHT

Table 3 summarises the proportion at risk of OSA, based on sleep scores (STOP-BANG score>3 and ESS>9) in aRHT/tRHT, overall and for the gender-based categories. The percentage at risk of OSA was also high (86% with 95% CI: 65% to 97%) in participants at high risk of tRHT. Although the proportions at risk of OSA were high in the RHT groups, the association between tRHT and OSA risk was not statistically significant (Chi square=0.465, df=1, p=0.495). The risk estimation showed that the risk of having OSA in the group at high risk of tRHT was 1.158 (95% CI: 0.981 to 1.367).

Table 3: Percentages of RHT categories for risk of OSA and daytime sleepiness.

aRHT: Apparent resistant hypertension, wcRHT: White coat resistant hypertension, pRHT: Pseudo resistant hypertension; tRHT: True resistant hypertension, SBQ: STOP-BANG questionnaire, ESS: Epworth Sleepiness Scale questionnaire score.

Discussion

The primary aim of this study was to determine the prevalence of tRHT among a Dunedin-based group diagnosed with hypertension and being pharmacologically managed with three or more medications (ie, with aRHT). Secondary aims were to describe the characteristics of a Dunedin-based cohort under 60 years of age with aRHT and to explore the risk of OSA among the individuals at high risk of tRHT. The study results suggest a high prevalence of tRHT in the group with aRHT and the possibility of a close association with OSA risk.

Prevalence of tRHT in RHT

The prevalence of risk of tRHT was high (88%) in the group with aRHT, higher than recently estimated values described in the systematic review by Noubiap et al.[[8]] One of the reasons for higher prevalence in our study may be the use of the lower threshold (130/80mmHg)[[2]] for the diagnostic value. Diagnosis using the lower thresholds will encourage practitioners to start treatment early, potentially enhancing the reversibility of the condition.[[4]] However, previous studies have shown large variations in the prevalence of RHT.[[18–20]] Thus, further studies are needed to confirm the exact prevalence with the diagnosis of tRHT considering all the conditions in the definition provided by the American Heart Association (2018).[[4]]

The association between RHT and OSA risk

Compared to other questionnaires, the STOP-BANG questionnaire score is a more valid and reliable measure to determine risk of OSA, especially in regard to specificity.[[21]] Our data indicated that the prevalence of risk of OSA was higher in both aRHT (88%) and high risk of tRHT (86%) groups in the study. Nearly half of the sample showed higher levels of daytime sleepiness (high ESS scores), and the energy and fatigue levels reported in the quality of life (SF-36) scores were low. Daytime sleepiness and fatigue are recognised as signs of OSA.[[21]] These findings may support the argument of there being a strong association between OSA and the condition RHT. Published studies using polysomnography have shown that the prevalence of OSA in RHT is more than 80%.[[19,22]] Although we did not use polysomnography to diagnose OSA, self-reported signs of fatigue and sleepiness in our cohort are strong indicators that OSA may have been present. A larger cohort study will be needed to confirm the prevalence of OSA in RHT.

The scatterplots of this study show no relationship between two variables (24h ABP and STOP-BANG score), which contrasts with previous studies that reported linear relationships and correlations between BP and sleep parameters (eg, the Apnoea Hypopnoea Index (AHI)).[[9,19]] Our small sample size may be the reason for not finding statistically significant results, though a large proportion of individuals at high risk of tRHT were also at high risk of OSA. Thus in-depth studies with large sample sizes are needed to determine such associations or to confirm whether there is a correlation between sleep scores and BP parameters in adults with RHT.

Sociodemographic and anthropometric characteristics

We specifically recruited participants who were 60 years and younger, leading to a relatively young mean age for the cohort (51.8±8.9 years). The mean number of years treated for hypertension (5.2±2.2 years) indicated that some participants may have been in their 40s when such medication was first prescribed. Thus, RHT can occur at a relatively young age without being caused by factors such as chronic kidney disease and without the known risks for hypertension associated with older age.[[4]] The relatively low number of self-reported comorbidities (such as diabetes) may be due to the young age range of the sample. Such low prevalence of diabetes in RHT groups is in agreement with the results of a previous study that included a large cohort of patients with RHT.[[20]] Thus, diabetes may not be highly prevalent in younger groups with RHT. Although Māori have a higher risk of hypertension and higher use of antihypertensive medication than New Zealand Europeans,[[3]] the study sample included only a small number of Māori (n= 2). The low Māori representation (8%) could be due to Māori comprising only 8.7% of the Otago population (according to 2018 census data).[[23]] The small number of Māori participants may be due to advertisements not being accessible or sufficiently engaging for them. Our future studies will seek consultation and input from Māori stakeholder groups to improve the relevance of the study and enhance strategies to recruit Māori participants specifically. Previous studies over the past decade have reported a low prevalence of smoking in cohorts with RHT. [[18,20]] Our study had similar findings. Alcohol intake and coffee consumption reported by our sample also did not exceed the recommended limits.[[24]]

The high BMI (>30kg/m[[2]]) and increased neck (>40cm for male and >38cm for female) and waist (>94cm for male and >80cm for female )[[25]] circumferences indicate higher body fat and the presence of visceral and abdominal adiposity respectively in the group.[[25]] This is in agreement with previous studies with larger sample sizes and similar designs that have explored the anthropometrics of individuals with RHT.[[19,20]] The New Zealand Ministry of Health[[25]] has previously identified that increased BMI (>25kg/m[[2]]) and waist circumference (>80cm for male and >94cm for female) are risk factors for high BP and poor cardiovascular health.[[25]] The sample in the present research reported markedly higher values compared to the values recommended by the New Zealand Ministry of Health.[[25]] Excess adipose tissue has the potential to activate the renin angiotensin aldosterone system, increase sympathetic activity, promote insulin and leptin resistance and increase endothelial dysfunction.[[4]]

Blood pressure characteristics

The BP values were similar to values reported in previous studies with similar cohorts in which the average BP was in the range 145–165/80–90mmHg.[[19,20]] The study group at risk of tRHT can be categorised under the uncontrolled RHT category as described in a recent guideline.[[26]] This situation could lead to prescribing more medications to manage BP and could result in refractory hypertension.[[4]] Also it is important to note that the mean office BP of the present study sample was lower than the reported 24h ABP value, indicating the importance of confirming BP over a 24h period.

Sleep and activity characteristics

Both self-reported and objectively measured physical activity levels in the study group were above the recommended values for gaining health benefits as defined by the Eating and Activity Guidelines of Ministry of Health and other prominent guidelines.[[27]] Despite this, the BP of the group was high, even though they were using three or more antihypertensive medications. This suggests that the presently recommended physical activity levels (150–300 min per week of moderate to vigorous physical activities[[27,28]]) may not be sufficient to benefit the population with RHT. Thus, further investigations are warranted to determine the BP response to physical activity in people with RHT.

The present study indicated that low quality of life was associated with the condition RHT. This is in line with the small amount of literature that has been published previously.[[29,30]]

Strengths

To our knowledge this was the first time a New Zealand population with aRHT was included in a comprehensive investigation. Thus this study has provided a valuable dataset. We used the most recent American (AHA/ACC)[[1]] and New Zealand updated[[2]] guidelines for diagnostic values for hypertension to determine the prevalence. The selected study sample was aged below 60 and this minimised the independent influence of ageing and associated predisposing factors for RHT. This comprehensive study design with appropriately calculated sample sizes will be an important model to use in future studies in the field.

Limitations

The sample size was adapted in several ways to ensure the study was feasible within the constraints of the PhD timeframe. We were unable to recruit the required sample size, and therefore the conclusions are limited to this cohort and need to be considered with some caution. To diagnose tRHT, the condition in the definition “maximum or maximally tolerated dose” was not used due to practical difficulties. Thus, the exact prevalence of tRHT may vary from the reported proportions. We determined the OSA risk according to the sleep scores, and we did not use overnight polysomnography, which is the measure recommended for diagnosing OSA. As the sample may not have been fully representative of the entire New Zealand population, generalisability of our results cannot be assumed.

Recommendations

The prevalence of risk of OSA was high in this sample, confirming the need to screen for risk of OSA and assess sleep patterns in individuals diagnosed with, or at high risk of, tRHT. Lifestyle interventions, particularly exercise programmes and/or longer recommended periods of exercise than those for the general population, will be needed for this specific cohort at high risk of tRHT. Referring patients with RHT to health professionals, such as physiotherapists, for specific individualised exercise will also be beneficial upon confirmation of the positive outcomes of such interventions. To confirm the results of the present study, a country-based, large cohort study that addresses the reported limitations is highly recommended.

Conclusions

The prevalence of individuals at high risk of tRHT among aRHT was 88%, and the proportion at risk of OSA among the high-risk group for tRHT was 86%. The prevalence of tRHT may be high and OSA could be highly associated with RHT. The group was obese with higher neck and waist circumferences compared to recommended values, suggesting abdominal and visceral adiposity. Though the BP was high in the group, individuals were involved in levels of physical activity within the range recommended by the New Zealand Ministry of Health. However, the quality of life for this group was low, with the scores having been influenced by the reduced scores for the physical activity components of the questionnaire.

Summary

Abstract

Aim

To determine the prevalence of individuals at high risk of true resistant hypertension (tRHT) in Dunedin-based adults <60 years diagnosed with hypertension and pharmacologically managed with three or more antihypertensive medications (ie, apparent resistant hypertension (aRHT)); to describe characteristics of those with aRHT; and to investigate the association between tRHT and obstructive sleep apnoea in the group.

Method

Participants with aRHT were recruited and data collected using standardised equipment and methodology. Characteristics were reported using descriptive statistics. The proportion (with 95% confidence intervals) of individuals at high risk of tRHT in individuals with aRHT was calculated.

Results

Twenty-five aRHT individuals participated (17 males; group mean age 51.8±8.9 years; body mass index 33.6±6.2 kg/m^2). Measures (mean ±SD) for neck circumferences for males were 41.9±4.9cm, females 37.3±3.1cm; waist circumferences for males were 108.4±15.2cm, females 105.2±17.3cm. Group systolic and diastolic 24h ambulatory blood pressure (mmHg) were 148.9±20.5 (95% CI: 140.4 to 157.4), 88.2±14.6 (95% CI: 82.2 to 94.2); office blood pressure were 140.8±18.3 (95% CI: 133.2 to 148.3), 83.5±12.1 (95% CI: 78.5 to 88.5). The prevalence of individuals at high risk of tRHT was 88% (95% CI: 69% to 98%); proportion of obstructive sleep apnoea (OSA) risk among tRHT group was 86% (95% CI 65%to 97%).

Conclusion

The prevalence of individuals at high risk of both tRHT and OSA risk was large in Dunedin-based adults diagnosed with aRHT. Anthropometric assessments indicated high abdominal and visceral adiposity. Group mean blood pressure values exceeded New Zealand’s hypertension diagnostic value, suggesting uncontrolled RHT.

Author Information

Suranga Dassanayake: Assistant Research Fellow; Physiotherapist, Centre for Health, Activity and Rehabilitation Research, School of Physiotherapy, University of Otago, New Zealand. Gisela Sole: Assoc/Professor; Physiotherapist Centre for Health, Activity and Rehabilitation Research, School of Physiotherapy, University of Otago, New Zealand. Gerard Wilkins: Assoc/Professor; Cardiologist, Department of Medicine, Dunedin School of Medicine, University of Otago, New Zealand. Margot Skinner: Senior Lecturer; Physiotherapist Centre for Health, Activity and Rehabilitation Research, School of Physiotherapy, University of Otago, New Zealand.

Acknowledgements

Correspondence

Dr Margot Skinner, Centre for Health, Activity and Rehabilitation Research, School of Physiotherapy, University of Otago, PO Box 56, Dunedin 9054, New Zealand, +64 3 479 7466 (tel), +64 3 479 8414 (fax)

Correspondence Email

margot.skinner@otago.ac.nz

Competing Interests

Nil.

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2) Ministry of Health New Zealand. Cardiovascular disease risk assessment and management for primary care [Internet]. Wellington, New Zealand: Ministry of Health; 2018 [cited 2018 Feb 14]. Available from: https://www.health.govt.nz/publication/cardiovascular-disease-risk-assessment-and-management-primary-care.

3) McLean RM, Williams S, Mann JI, et al. Blood pressure and hypertension in New Zealand: results from the 2008/09 Adult Nutrition Survey. N Z Med J. 2013;126(1372):66-79.

4) Carey RM, Calhoun DA, Bakris GL, et al. Resistant hypertension: detection, evaluation, and management: a scientific statement from the American Heart Association. Hypertension. 2018;72(5):e53-e90.

5) Smith SM. Epidemiology, prognosis, and treatment of resistant hypertension. Pharmacotherapy. 2013;33(10):1071-86.

6) Muntner P, Carey RM, Gidding S, et al. Potential US population impact of the 2017 ACC/AHA high blood pressure guideline. J Am Coll Cardiol. 2018;71(2):109-18.

7) Williams B, Mancia G, Spiering W, et al. 2018 ESC/ESH guidelines for the management of arterial hypertension. Eur Heart J. 2018;39(33):3021-104.

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10) Epton MJ, Kelly PT, Shand BI, et al. Development and outcomes of a primary care-based sleep assessment service in Canterbury, New Zealand. NPJ Prim Care Respir Med. 2017;27(1):26.

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Hypertension is one of the key risk factors for cardiovascular disease.[[1,2]] In New Zealand Māori have the highest level of risk for hypertension of all ethnic groups.[[3]] Although the first line of treatment for hypertension is medication, blood pressure (BP) is controlled by medications alone in only a fraction of patients.[[4]] Resistant hypertension (RHT) is a subset of hypertension, defined in the Scientific Statement of the American Heart Association[[4]] as “BP remaining above the goal BP in spite of concurrent use of three or more antihypertensive agents, including a diuretic.”[[4]] Currently RHT is recognised as an increasingly common clinical problem, and higher fatal event rates have been identified in RHT compared to hypertension.[[5]] Ambulatory BP over 24h (24h ABP) is recommended to exclude the “white coat/pseudo” (higher clinic BP and normal day-to-day BP), or to “mask” (normal clinic BP and higher day-to-day BP) effects and diagnose RHT, which can be termed as “true RHT” (tRHT).[[6]] RHT diagnosed but not excluding white coat/pseudo or masked hypertension is termed “apparent RHT” (aRHT). Use of country-based, recommended BP diagnostic values and 24h ABP to estimate the prevalence in the relevant population may be important for accessing relevant healthcare and, thereby, to help reduce morbidity and mortality risk.

Based on the BP diagnostic value 140/90 mmHg,[[7]] the estimated global prevalence of aRHT among populations with hypertension is 14.7%, and the estimated prevalence of tRHT is 10.3%.[[8]] On this basis the prevalence of tRHT among the population with aRHT can be calculated as approximately 70%.

Studies that have investigated the prevalence of any type of RHT are limited to Western Pacific (n=4) and Oceania (n=1) geographic regions.[[8]] There are currently no published data on the prevalence of any type of RHT in New Zealand. Māori have a 15% higher use of antihypertensive medication compared to New Zealand Europeans,[[3]] and thus RHT could be high in Māori.

Obstructive sleep apnoea (OSA) and RHT have a close, and strong, bidirectional relationship: each compounds the other.[[4,9]] In New Zealand, as in many other countries, OSA remains under-diagnosed.[[10]] Approximately 70%–80% of adults diagnosed with OSA also have RHT, and 30%–50% with RHT have OSA.[[9]] Thus studies are needed to determine the prevalence of tRHT and its association with OSA in New Zealand.

The aims of this study were, firstly, to explore the prevalence of individuals at high risk of tRHT in a sample population with aRHT, and secondly to describe the characteristics of the study group in order to determine whether a high risk of OSA is associated with individuals at high risk of tRHT in a New Zealand cohort. The outcomes of the study may be beneficial to improve diagnosis, as well as access to healthcare and associated healthcare costs.

Methods

This observational study was registered in the Australia New Zealand Clinical Trial Registry (ACTRN12618001110279p) and ethics approval was obtained from the Health and Disability Ethics Committees, New Zealand Ministry of Health (18/CEN/141).

Study setting and population

The study participants comprised Dunedin-based adults 60 years and younger diagnosed with aRHT.

Inclusion and exclusion criteria

Adults aged 18–60 years diagnosed with primary hypertension and managed pharmacologically with three or more antihypertensive medications, referred to as “aRHT,” were included. Individuals were excluded (not referred by clinicians as potential study participants) if they were diagnosed with acute or chronic kidney disease, had a metabolic disorder such as Cushing’s syndrome, were critically ill or were pregnant.

Sample size

The population was drawn from the Ministry of Health Pharmaceutical Collection Warehouse, via the Best Practice Advocacy Centre (bpac), New Zealand. That database revealed 559 adults in Dunedin under 60 years with hypertension and pharmacologically managed with three or more antihypertensive medications (aRHT). To estimate the prevalence with precision of a 5% margin of error for that finite population size, 228 participants would have been required. A pragmatic decision was made to undertake the study with an adjusted sample size by using an approximated prevalence of 10% and a 10% margin of error. Under these assumptions, the required sample size was estimated to be 35, requiring 70 invitees with an estimated 50% response rate.

Recruitment procedure

The cohort was recruited through general practitioner (GP) referrals and advertising posters. Twenty-five individuals who fulfilled the inclusion criteria consented to participating in the study. After providing informed consent, participants’ demographic data, general health and social habits, self-reported physical activity level, adherence to medications (Morisky Medication Adherence Scale), quality of life (SF-36) and OSA risk (Epworth Sleepiness Scale (ESS) and STOP-BANG questionnaire) were obtained and recorded. The measurements shown in Table 1 were obtained using standardised, calibrated equipment and guidelines.

Outcome measures

The primary outcome, 24h ABP, was recorded using an Ultralite 90217A ABP monitor and 92506 ABP Report Management System (Spacelab Healthcare, WA, USA) in accordance with the instructions in the user manual. The device was fitted to each participant on completion of their questionnaires and anthropometric measurements. The devices were removed at the same time the following day, after recording for 24 hours (day and night). Office/clinic BP was measured at the first visit in accordance with the American Heart Association/American College of Cardiology (AHA/ACC) 2017[[1]] guidelines using an Omron digital BP monitor (HEM 7322, Netherlands).

Secondary outcomes

Scores for ESS and STOP-BANG questionnaires were used to determine levels of excessive daytime sleepiness and risk of OSA. Levels of physical activity and sleep parameters were captured by the ActiGraph GT3XPB, Activitrax monitor (Pensacola, Florida, USA) over a seven-day period in accordance with the instructions in the user manual. The device, an activity monitor fitted on the non-dominant wrist of each participant, was worn continuously for seven days and nights to record their activity and sleep data (Table 1). Each participant completed a six-minute walk test (6MWT) to determine their cardio-respiratory fitness. The short form 36 (SF-36) was administered to determine participants’ quality of life. Collection of anthropometric data (Table 1) followed the protocols documented in the Exercise and Sports Science Australia (ESSA) manual and used standardised calibrated equipment (eg, Seca 876 weighing scale, Seca 217 stadiometer, Seca 201 anthropometric measuring tape) (Table 1).

Statistical analysis

Statistical Package for Social Sciences (SPSS) (IBM SPSS version 25.0 for Windows, NY, USA) was used to analyse the data.[[11]] Characteristics of the sample were reported as means for continuous data and as percentages for categorical data. The proportion with tRHT in the sample population with aRHT was calculated with confidence intervals. Scatterplots were used for BP values and sleep scores to determine the existence of any associations between the variables. The scatterplots did not show a relationship, and thus the correlational analysis was not conducted. Cross-tabulation was used to determine the relationship between tRHT diagnosis and risk of OSA.

Results

Characteristics of the population with RHT

The participants’ mean age was 51.8±8.9 years (range 34–60 years). The majority (n=18: 72%) identified as New Zealand Europeans, two as Māori (8%) and the rest as other ethnicities. On average, the participants had been treated for 5.2±2.2 years for hypertension and the mean number of prescribed medications was 3.2±0.7. The participants showed good adherence (80%) to medication according to the Morisky Medication Adherence Scale.[[12]] The majority (n=16: 64%) of participants were non-smokers. Twenty (80%) were consumers of alcohol (mean number of drinks per week 8.6±12.7) and 18 (72%) were coffee drinkers (mean number of cups 2.5±2.6 per day). Ten participants (40%) used medication for hyperlipidaemia, seven (28%) had diabetes and four (16%) had both conditions. Two had previously had a mild cerebro-vascular accident and one reported a previous history of a myocardial infarction. Means and confidence intervals for BP, anthropometrics, sleep and activity parameters are summarised in Table 2.

Table 1: Blood pressure, sleep and activity parameters of the group. View Table 1.

The mean 24h ABP value of the sample was above the American (AHA/ACC)[[1]] and New Zealand[[2]] diagnostic value for stage II hypertension (>140/90mmHg). The mean daytime sleepiness of the sample was below the cut-off value for excessive daytime sleepiness (ESS score >9)[[13]] in the group, suggesting a lower risk of daytime sleepiness. The objective measurements of sleep showed high mean sleep efficiency (>80%),[[14]] and the mean total sleep time was within the recommended range (7–9h) for an adult.[[15]] Twenty-three participants (92%) reported that they were regularly undertaking exercise or physical activities (mean 4.5±2.2 times per week) within the recommended duration (mean 4.5±2.6 hours per week). The mean moderate to vigorous physical activity (MVPA) duration per week was 12.9% of total time. MVPA per day and step count were above the recommended guidelines (150–300 minutes per week, and over 10,000 steps), although the group reported a higher total sedentary time per week (Table 2). The mean value for Freedson (1998) activity bouts,[[16]] the MVPA with a minimum duration of 10 minutes, was 442.3±386.1 minutes per week, a relatively low value. In contrast, for sedentary bouts, the sedentary time comprising more than 10 minutes[[16]] was reported as 3,226.2±995.0 minutes per week, which is several times higher than Freedson bouts (Table 2).

Overall quality of life for the group was low (SF 36 score 66.7±19.8: 95% CI: 58.6 to 74.9). Particular components of the SF-36-role limitation due to physical health (68.0±40.5), energy/fatigue (53.0±25.4), health change (51.0±26.5) and general health (49.8±20.6) each contributed to the overall low quality of life score for the group.

Prevalence of individuals at high risk of tRHT

The mean office BP values for the group were above 130/80 mmHg, indicating that all the participants (n=25) could be categorised as aRHT.[[1,2,17]] The prevalence of high risk of tRHT among the group with RHT was 88% (95% CI: 68.8 to 97.5). The percentages for the categories of RHT based on the 24h ABP for the group are summarised in Table 2.

Table 2: Approximate prevalence of resistant hypertension categories (diagnosed based on 24h ABP).

nRHT: Non-resistant hypertension, aRHT: Apparent resistant hypertension, tRHT: True resistant hypertension, pRHT: Pseudo resistant hypertension, wcRHt: White coat resistant hypertension.

OSA risk in individuals at high risk of tRHT

Table 3 summarises the proportion at risk of OSA, based on sleep scores (STOP-BANG score>3 and ESS>9) in aRHT/tRHT, overall and for the gender-based categories. The percentage at risk of OSA was also high (86% with 95% CI: 65% to 97%) in participants at high risk of tRHT. Although the proportions at risk of OSA were high in the RHT groups, the association between tRHT and OSA risk was not statistically significant (Chi square=0.465, df=1, p=0.495). The risk estimation showed that the risk of having OSA in the group at high risk of tRHT was 1.158 (95% CI: 0.981 to 1.367).

Table 3: Percentages of RHT categories for risk of OSA and daytime sleepiness.

aRHT: Apparent resistant hypertension, wcRHT: White coat resistant hypertension, pRHT: Pseudo resistant hypertension; tRHT: True resistant hypertension, SBQ: STOP-BANG questionnaire, ESS: Epworth Sleepiness Scale questionnaire score.

Discussion

The primary aim of this study was to determine the prevalence of tRHT among a Dunedin-based group diagnosed with hypertension and being pharmacologically managed with three or more medications (ie, with aRHT). Secondary aims were to describe the characteristics of a Dunedin-based cohort under 60 years of age with aRHT and to explore the risk of OSA among the individuals at high risk of tRHT. The study results suggest a high prevalence of tRHT in the group with aRHT and the possibility of a close association with OSA risk.

Prevalence of tRHT in RHT

The prevalence of risk of tRHT was high (88%) in the group with aRHT, higher than recently estimated values described in the systematic review by Noubiap et al.[[8]] One of the reasons for higher prevalence in our study may be the use of the lower threshold (130/80mmHg)[[2]] for the diagnostic value. Diagnosis using the lower thresholds will encourage practitioners to start treatment early, potentially enhancing the reversibility of the condition.[[4]] However, previous studies have shown large variations in the prevalence of RHT.[[18–20]] Thus, further studies are needed to confirm the exact prevalence with the diagnosis of tRHT considering all the conditions in the definition provided by the American Heart Association (2018).[[4]]

The association between RHT and OSA risk

Compared to other questionnaires, the STOP-BANG questionnaire score is a more valid and reliable measure to determine risk of OSA, especially in regard to specificity.[[21]] Our data indicated that the prevalence of risk of OSA was higher in both aRHT (88%) and high risk of tRHT (86%) groups in the study. Nearly half of the sample showed higher levels of daytime sleepiness (high ESS scores), and the energy and fatigue levels reported in the quality of life (SF-36) scores were low. Daytime sleepiness and fatigue are recognised as signs of OSA.[[21]] These findings may support the argument of there being a strong association between OSA and the condition RHT. Published studies using polysomnography have shown that the prevalence of OSA in RHT is more than 80%.[[19,22]] Although we did not use polysomnography to diagnose OSA, self-reported signs of fatigue and sleepiness in our cohort are strong indicators that OSA may have been present. A larger cohort study will be needed to confirm the prevalence of OSA in RHT.

The scatterplots of this study show no relationship between two variables (24h ABP and STOP-BANG score), which contrasts with previous studies that reported linear relationships and correlations between BP and sleep parameters (eg, the Apnoea Hypopnoea Index (AHI)).[[9,19]] Our small sample size may be the reason for not finding statistically significant results, though a large proportion of individuals at high risk of tRHT were also at high risk of OSA. Thus in-depth studies with large sample sizes are needed to determine such associations or to confirm whether there is a correlation between sleep scores and BP parameters in adults with RHT.

Sociodemographic and anthropometric characteristics

We specifically recruited participants who were 60 years and younger, leading to a relatively young mean age for the cohort (51.8±8.9 years). The mean number of years treated for hypertension (5.2±2.2 years) indicated that some participants may have been in their 40s when such medication was first prescribed. Thus, RHT can occur at a relatively young age without being caused by factors such as chronic kidney disease and without the known risks for hypertension associated with older age.[[4]] The relatively low number of self-reported comorbidities (such as diabetes) may be due to the young age range of the sample. Such low prevalence of diabetes in RHT groups is in agreement with the results of a previous study that included a large cohort of patients with RHT.[[20]] Thus, diabetes may not be highly prevalent in younger groups with RHT. Although Māori have a higher risk of hypertension and higher use of antihypertensive medication than New Zealand Europeans,[[3]] the study sample included only a small number of Māori (n= 2). The low Māori representation (8%) could be due to Māori comprising only 8.7% of the Otago population (according to 2018 census data).[[23]] The small number of Māori participants may be due to advertisements not being accessible or sufficiently engaging for them. Our future studies will seek consultation and input from Māori stakeholder groups to improve the relevance of the study and enhance strategies to recruit Māori participants specifically. Previous studies over the past decade have reported a low prevalence of smoking in cohorts with RHT. [[18,20]] Our study had similar findings. Alcohol intake and coffee consumption reported by our sample also did not exceed the recommended limits.[[24]]

The high BMI (>30kg/m[[2]]) and increased neck (>40cm for male and >38cm for female) and waist (>94cm for male and >80cm for female )[[25]] circumferences indicate higher body fat and the presence of visceral and abdominal adiposity respectively in the group.[[25]] This is in agreement with previous studies with larger sample sizes and similar designs that have explored the anthropometrics of individuals with RHT.[[19,20]] The New Zealand Ministry of Health[[25]] has previously identified that increased BMI (>25kg/m[[2]]) and waist circumference (>80cm for male and >94cm for female) are risk factors for high BP and poor cardiovascular health.[[25]] The sample in the present research reported markedly higher values compared to the values recommended by the New Zealand Ministry of Health.[[25]] Excess adipose tissue has the potential to activate the renin angiotensin aldosterone system, increase sympathetic activity, promote insulin and leptin resistance and increase endothelial dysfunction.[[4]]

Blood pressure characteristics

The BP values were similar to values reported in previous studies with similar cohorts in which the average BP was in the range 145–165/80–90mmHg.[[19,20]] The study group at risk of tRHT can be categorised under the uncontrolled RHT category as described in a recent guideline.[[26]] This situation could lead to prescribing more medications to manage BP and could result in refractory hypertension.[[4]] Also it is important to note that the mean office BP of the present study sample was lower than the reported 24h ABP value, indicating the importance of confirming BP over a 24h period.

Sleep and activity characteristics

Both self-reported and objectively measured physical activity levels in the study group were above the recommended values for gaining health benefits as defined by the Eating and Activity Guidelines of Ministry of Health and other prominent guidelines.[[27]] Despite this, the BP of the group was high, even though they were using three or more antihypertensive medications. This suggests that the presently recommended physical activity levels (150–300 min per week of moderate to vigorous physical activities[[27,28]]) may not be sufficient to benefit the population with RHT. Thus, further investigations are warranted to determine the BP response to physical activity in people with RHT.

The present study indicated that low quality of life was associated with the condition RHT. This is in line with the small amount of literature that has been published previously.[[29,30]]

Strengths

To our knowledge this was the first time a New Zealand population with aRHT was included in a comprehensive investigation. Thus this study has provided a valuable dataset. We used the most recent American (AHA/ACC)[[1]] and New Zealand updated[[2]] guidelines for diagnostic values for hypertension to determine the prevalence. The selected study sample was aged below 60 and this minimised the independent influence of ageing and associated predisposing factors for RHT. This comprehensive study design with appropriately calculated sample sizes will be an important model to use in future studies in the field.

Limitations

The sample size was adapted in several ways to ensure the study was feasible within the constraints of the PhD timeframe. We were unable to recruit the required sample size, and therefore the conclusions are limited to this cohort and need to be considered with some caution. To diagnose tRHT, the condition in the definition “maximum or maximally tolerated dose” was not used due to practical difficulties. Thus, the exact prevalence of tRHT may vary from the reported proportions. We determined the OSA risk according to the sleep scores, and we did not use overnight polysomnography, which is the measure recommended for diagnosing OSA. As the sample may not have been fully representative of the entire New Zealand population, generalisability of our results cannot be assumed.

Recommendations

The prevalence of risk of OSA was high in this sample, confirming the need to screen for risk of OSA and assess sleep patterns in individuals diagnosed with, or at high risk of, tRHT. Lifestyle interventions, particularly exercise programmes and/or longer recommended periods of exercise than those for the general population, will be needed for this specific cohort at high risk of tRHT. Referring patients with RHT to health professionals, such as physiotherapists, for specific individualised exercise will also be beneficial upon confirmation of the positive outcomes of such interventions. To confirm the results of the present study, a country-based, large cohort study that addresses the reported limitations is highly recommended.

Conclusions

The prevalence of individuals at high risk of tRHT among aRHT was 88%, and the proportion at risk of OSA among the high-risk group for tRHT was 86%. The prevalence of tRHT may be high and OSA could be highly associated with RHT. The group was obese with higher neck and waist circumferences compared to recommended values, suggesting abdominal and visceral adiposity. Though the BP was high in the group, individuals were involved in levels of physical activity within the range recommended by the New Zealand Ministry of Health. However, the quality of life for this group was low, with the scores having been influenced by the reduced scores for the physical activity components of the questionnaire.

Summary

Abstract

Aim

To determine the prevalence of individuals at high risk of true resistant hypertension (tRHT) in Dunedin-based adults <60 years diagnosed with hypertension and pharmacologically managed with three or more antihypertensive medications (ie, apparent resistant hypertension (aRHT)); to describe characteristics of those with aRHT; and to investigate the association between tRHT and obstructive sleep apnoea in the group.

Method

Participants with aRHT were recruited and data collected using standardised equipment and methodology. Characteristics were reported using descriptive statistics. The proportion (with 95% confidence intervals) of individuals at high risk of tRHT in individuals with aRHT was calculated.

Results

Twenty-five aRHT individuals participated (17 males; group mean age 51.8±8.9 years; body mass index 33.6±6.2 kg/m^2). Measures (mean ±SD) for neck circumferences for males were 41.9±4.9cm, females 37.3±3.1cm; waist circumferences for males were 108.4±15.2cm, females 105.2±17.3cm. Group systolic and diastolic 24h ambulatory blood pressure (mmHg) were 148.9±20.5 (95% CI: 140.4 to 157.4), 88.2±14.6 (95% CI: 82.2 to 94.2); office blood pressure were 140.8±18.3 (95% CI: 133.2 to 148.3), 83.5±12.1 (95% CI: 78.5 to 88.5). The prevalence of individuals at high risk of tRHT was 88% (95% CI: 69% to 98%); proportion of obstructive sleep apnoea (OSA) risk among tRHT group was 86% (95% CI 65%to 97%).

Conclusion

The prevalence of individuals at high risk of both tRHT and OSA risk was large in Dunedin-based adults diagnosed with aRHT. Anthropometric assessments indicated high abdominal and visceral adiposity. Group mean blood pressure values exceeded New Zealand’s hypertension diagnostic value, suggesting uncontrolled RHT.

Author Information

Suranga Dassanayake: Assistant Research Fellow; Physiotherapist, Centre for Health, Activity and Rehabilitation Research, School of Physiotherapy, University of Otago, New Zealand. Gisela Sole: Assoc/Professor; Physiotherapist Centre for Health, Activity and Rehabilitation Research, School of Physiotherapy, University of Otago, New Zealand. Gerard Wilkins: Assoc/Professor; Cardiologist, Department of Medicine, Dunedin School of Medicine, University of Otago, New Zealand. Margot Skinner: Senior Lecturer; Physiotherapist Centre for Health, Activity and Rehabilitation Research, School of Physiotherapy, University of Otago, New Zealand.

Acknowledgements

Correspondence

Dr Margot Skinner, Centre for Health, Activity and Rehabilitation Research, School of Physiotherapy, University of Otago, PO Box 56, Dunedin 9054, New Zealand, +64 3 479 7466 (tel), +64 3 479 8414 (fax)

Correspondence Email

margot.skinner@otago.ac.nz

Competing Interests

Nil.

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2) Ministry of Health New Zealand. Cardiovascular disease risk assessment and management for primary care [Internet]. Wellington, New Zealand: Ministry of Health; 2018 [cited 2018 Feb 14]. Available from: https://www.health.govt.nz/publication/cardiovascular-disease-risk-assessment-and-management-primary-care.

3) McLean RM, Williams S, Mann JI, et al. Blood pressure and hypertension in New Zealand: results from the 2008/09 Adult Nutrition Survey. N Z Med J. 2013;126(1372):66-79.

4) Carey RM, Calhoun DA, Bakris GL, et al. Resistant hypertension: detection, evaluation, and management: a scientific statement from the American Heart Association. Hypertension. 2018;72(5):e53-e90.

5) Smith SM. Epidemiology, prognosis, and treatment of resistant hypertension. Pharmacotherapy. 2013;33(10):1071-86.

6) Muntner P, Carey RM, Gidding S, et al. Potential US population impact of the 2017 ACC/AHA high blood pressure guideline. J Am Coll Cardiol. 2018;71(2):109-18.

7) Williams B, Mancia G, Spiering W, et al. 2018 ESC/ESH guidelines for the management of arterial hypertension. Eur Heart J. 2018;39(33):3021-104.

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10) Epton MJ, Kelly PT, Shand BI, et al. Development and outcomes of a primary care-based sleep assessment service in Canterbury, New Zealand. NPJ Prim Care Respir Med. 2017;27(1):26.

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Hypertension is one of the key risk factors for cardiovascular disease.[[1,2]] In New Zealand Māori have the highest level of risk for hypertension of all ethnic groups.[[3]] Although the first line of treatment for hypertension is medication, blood pressure (BP) is controlled by medications alone in only a fraction of patients.[[4]] Resistant hypertension (RHT) is a subset of hypertension, defined in the Scientific Statement of the American Heart Association[[4]] as “BP remaining above the goal BP in spite of concurrent use of three or more antihypertensive agents, including a diuretic.”[[4]] Currently RHT is recognised as an increasingly common clinical problem, and higher fatal event rates have been identified in RHT compared to hypertension.[[5]] Ambulatory BP over 24h (24h ABP) is recommended to exclude the “white coat/pseudo” (higher clinic BP and normal day-to-day BP), or to “mask” (normal clinic BP and higher day-to-day BP) effects and diagnose RHT, which can be termed as “true RHT” (tRHT).[[6]] RHT diagnosed but not excluding white coat/pseudo or masked hypertension is termed “apparent RHT” (aRHT). Use of country-based, recommended BP diagnostic values and 24h ABP to estimate the prevalence in the relevant population may be important for accessing relevant healthcare and, thereby, to help reduce morbidity and mortality risk.

Based on the BP diagnostic value 140/90 mmHg,[[7]] the estimated global prevalence of aRHT among populations with hypertension is 14.7%, and the estimated prevalence of tRHT is 10.3%.[[8]] On this basis the prevalence of tRHT among the population with aRHT can be calculated as approximately 70%.

Studies that have investigated the prevalence of any type of RHT are limited to Western Pacific (n=4) and Oceania (n=1) geographic regions.[[8]] There are currently no published data on the prevalence of any type of RHT in New Zealand. Māori have a 15% higher use of antihypertensive medication compared to New Zealand Europeans,[[3]] and thus RHT could be high in Māori.

Obstructive sleep apnoea (OSA) and RHT have a close, and strong, bidirectional relationship: each compounds the other.[[4,9]] In New Zealand, as in many other countries, OSA remains under-diagnosed.[[10]] Approximately 70%–80% of adults diagnosed with OSA also have RHT, and 30%–50% with RHT have OSA.[[9]] Thus studies are needed to determine the prevalence of tRHT and its association with OSA in New Zealand.

The aims of this study were, firstly, to explore the prevalence of individuals at high risk of tRHT in a sample population with aRHT, and secondly to describe the characteristics of the study group in order to determine whether a high risk of OSA is associated with individuals at high risk of tRHT in a New Zealand cohort. The outcomes of the study may be beneficial to improve diagnosis, as well as access to healthcare and associated healthcare costs.

Methods

This observational study was registered in the Australia New Zealand Clinical Trial Registry (ACTRN12618001110279p) and ethics approval was obtained from the Health and Disability Ethics Committees, New Zealand Ministry of Health (18/CEN/141).

Study setting and population

The study participants comprised Dunedin-based adults 60 years and younger diagnosed with aRHT.

Inclusion and exclusion criteria

Adults aged 18–60 years diagnosed with primary hypertension and managed pharmacologically with three or more antihypertensive medications, referred to as “aRHT,” were included. Individuals were excluded (not referred by clinicians as potential study participants) if they were diagnosed with acute or chronic kidney disease, had a metabolic disorder such as Cushing’s syndrome, were critically ill or were pregnant.

Sample size

The population was drawn from the Ministry of Health Pharmaceutical Collection Warehouse, via the Best Practice Advocacy Centre (bpac), New Zealand. That database revealed 559 adults in Dunedin under 60 years with hypertension and pharmacologically managed with three or more antihypertensive medications (aRHT). To estimate the prevalence with precision of a 5% margin of error for that finite population size, 228 participants would have been required. A pragmatic decision was made to undertake the study with an adjusted sample size by using an approximated prevalence of 10% and a 10% margin of error. Under these assumptions, the required sample size was estimated to be 35, requiring 70 invitees with an estimated 50% response rate.

Recruitment procedure

The cohort was recruited through general practitioner (GP) referrals and advertising posters. Twenty-five individuals who fulfilled the inclusion criteria consented to participating in the study. After providing informed consent, participants’ demographic data, general health and social habits, self-reported physical activity level, adherence to medications (Morisky Medication Adherence Scale), quality of life (SF-36) and OSA risk (Epworth Sleepiness Scale (ESS) and STOP-BANG questionnaire) were obtained and recorded. The measurements shown in Table 1 were obtained using standardised, calibrated equipment and guidelines.

Outcome measures

The primary outcome, 24h ABP, was recorded using an Ultralite 90217A ABP monitor and 92506 ABP Report Management System (Spacelab Healthcare, WA, USA) in accordance with the instructions in the user manual. The device was fitted to each participant on completion of their questionnaires and anthropometric measurements. The devices were removed at the same time the following day, after recording for 24 hours (day and night). Office/clinic BP was measured at the first visit in accordance with the American Heart Association/American College of Cardiology (AHA/ACC) 2017[[1]] guidelines using an Omron digital BP monitor (HEM 7322, Netherlands).

Secondary outcomes

Scores for ESS and STOP-BANG questionnaires were used to determine levels of excessive daytime sleepiness and risk of OSA. Levels of physical activity and sleep parameters were captured by the ActiGraph GT3XPB, Activitrax monitor (Pensacola, Florida, USA) over a seven-day period in accordance with the instructions in the user manual. The device, an activity monitor fitted on the non-dominant wrist of each participant, was worn continuously for seven days and nights to record their activity and sleep data (Table 1). Each participant completed a six-minute walk test (6MWT) to determine their cardio-respiratory fitness. The short form 36 (SF-36) was administered to determine participants’ quality of life. Collection of anthropometric data (Table 1) followed the protocols documented in the Exercise and Sports Science Australia (ESSA) manual and used standardised calibrated equipment (eg, Seca 876 weighing scale, Seca 217 stadiometer, Seca 201 anthropometric measuring tape) (Table 1).

Statistical analysis

Statistical Package for Social Sciences (SPSS) (IBM SPSS version 25.0 for Windows, NY, USA) was used to analyse the data.[[11]] Characteristics of the sample were reported as means for continuous data and as percentages for categorical data. The proportion with tRHT in the sample population with aRHT was calculated with confidence intervals. Scatterplots were used for BP values and sleep scores to determine the existence of any associations between the variables. The scatterplots did not show a relationship, and thus the correlational analysis was not conducted. Cross-tabulation was used to determine the relationship between tRHT diagnosis and risk of OSA.

Results

Characteristics of the population with RHT

The participants’ mean age was 51.8±8.9 years (range 34–60 years). The majority (n=18: 72%) identified as New Zealand Europeans, two as Māori (8%) and the rest as other ethnicities. On average, the participants had been treated for 5.2±2.2 years for hypertension and the mean number of prescribed medications was 3.2±0.7. The participants showed good adherence (80%) to medication according to the Morisky Medication Adherence Scale.[[12]] The majority (n=16: 64%) of participants were non-smokers. Twenty (80%) were consumers of alcohol (mean number of drinks per week 8.6±12.7) and 18 (72%) were coffee drinkers (mean number of cups 2.5±2.6 per day). Ten participants (40%) used medication for hyperlipidaemia, seven (28%) had diabetes and four (16%) had both conditions. Two had previously had a mild cerebro-vascular accident and one reported a previous history of a myocardial infarction. Means and confidence intervals for BP, anthropometrics, sleep and activity parameters are summarised in Table 2.

Table 1: Blood pressure, sleep and activity parameters of the group. View Table 1.

The mean 24h ABP value of the sample was above the American (AHA/ACC)[[1]] and New Zealand[[2]] diagnostic value for stage II hypertension (>140/90mmHg). The mean daytime sleepiness of the sample was below the cut-off value for excessive daytime sleepiness (ESS score >9)[[13]] in the group, suggesting a lower risk of daytime sleepiness. The objective measurements of sleep showed high mean sleep efficiency (>80%),[[14]] and the mean total sleep time was within the recommended range (7–9h) for an adult.[[15]] Twenty-three participants (92%) reported that they were regularly undertaking exercise or physical activities (mean 4.5±2.2 times per week) within the recommended duration (mean 4.5±2.6 hours per week). The mean moderate to vigorous physical activity (MVPA) duration per week was 12.9% of total time. MVPA per day and step count were above the recommended guidelines (150–300 minutes per week, and over 10,000 steps), although the group reported a higher total sedentary time per week (Table 2). The mean value for Freedson (1998) activity bouts,[[16]] the MVPA with a minimum duration of 10 minutes, was 442.3±386.1 minutes per week, a relatively low value. In contrast, for sedentary bouts, the sedentary time comprising more than 10 minutes[[16]] was reported as 3,226.2±995.0 minutes per week, which is several times higher than Freedson bouts (Table 2).

Overall quality of life for the group was low (SF 36 score 66.7±19.8: 95% CI: 58.6 to 74.9). Particular components of the SF-36-role limitation due to physical health (68.0±40.5), energy/fatigue (53.0±25.4), health change (51.0±26.5) and general health (49.8±20.6) each contributed to the overall low quality of life score for the group.

Prevalence of individuals at high risk of tRHT

The mean office BP values for the group were above 130/80 mmHg, indicating that all the participants (n=25) could be categorised as aRHT.[[1,2,17]] The prevalence of high risk of tRHT among the group with RHT was 88% (95% CI: 68.8 to 97.5). The percentages for the categories of RHT based on the 24h ABP for the group are summarised in Table 2.

Table 2: Approximate prevalence of resistant hypertension categories (diagnosed based on 24h ABP).

nRHT: Non-resistant hypertension, aRHT: Apparent resistant hypertension, tRHT: True resistant hypertension, pRHT: Pseudo resistant hypertension, wcRHt: White coat resistant hypertension.

OSA risk in individuals at high risk of tRHT

Table 3 summarises the proportion at risk of OSA, based on sleep scores (STOP-BANG score>3 and ESS>9) in aRHT/tRHT, overall and for the gender-based categories. The percentage at risk of OSA was also high (86% with 95% CI: 65% to 97%) in participants at high risk of tRHT. Although the proportions at risk of OSA were high in the RHT groups, the association between tRHT and OSA risk was not statistically significant (Chi square=0.465, df=1, p=0.495). The risk estimation showed that the risk of having OSA in the group at high risk of tRHT was 1.158 (95% CI: 0.981 to 1.367).

Table 3: Percentages of RHT categories for risk of OSA and daytime sleepiness.

aRHT: Apparent resistant hypertension, wcRHT: White coat resistant hypertension, pRHT: Pseudo resistant hypertension; tRHT: True resistant hypertension, SBQ: STOP-BANG questionnaire, ESS: Epworth Sleepiness Scale questionnaire score.

Discussion

The primary aim of this study was to determine the prevalence of tRHT among a Dunedin-based group diagnosed with hypertension and being pharmacologically managed with three or more medications (ie, with aRHT). Secondary aims were to describe the characteristics of a Dunedin-based cohort under 60 years of age with aRHT and to explore the risk of OSA among the individuals at high risk of tRHT. The study results suggest a high prevalence of tRHT in the group with aRHT and the possibility of a close association with OSA risk.

Prevalence of tRHT in RHT

The prevalence of risk of tRHT was high (88%) in the group with aRHT, higher than recently estimated values described in the systematic review by Noubiap et al.[[8]] One of the reasons for higher prevalence in our study may be the use of the lower threshold (130/80mmHg)[[2]] for the diagnostic value. Diagnosis using the lower thresholds will encourage practitioners to start treatment early, potentially enhancing the reversibility of the condition.[[4]] However, previous studies have shown large variations in the prevalence of RHT.[[18–20]] Thus, further studies are needed to confirm the exact prevalence with the diagnosis of tRHT considering all the conditions in the definition provided by the American Heart Association (2018).[[4]]

The association between RHT and OSA risk

Compared to other questionnaires, the STOP-BANG questionnaire score is a more valid and reliable measure to determine risk of OSA, especially in regard to specificity.[[21]] Our data indicated that the prevalence of risk of OSA was higher in both aRHT (88%) and high risk of tRHT (86%) groups in the study. Nearly half of the sample showed higher levels of daytime sleepiness (high ESS scores), and the energy and fatigue levels reported in the quality of life (SF-36) scores were low. Daytime sleepiness and fatigue are recognised as signs of OSA.[[21]] These findings may support the argument of there being a strong association between OSA and the condition RHT. Published studies using polysomnography have shown that the prevalence of OSA in RHT is more than 80%.[[19,22]] Although we did not use polysomnography to diagnose OSA, self-reported signs of fatigue and sleepiness in our cohort are strong indicators that OSA may have been present. A larger cohort study will be needed to confirm the prevalence of OSA in RHT.

The scatterplots of this study show no relationship between two variables (24h ABP and STOP-BANG score), which contrasts with previous studies that reported linear relationships and correlations between BP and sleep parameters (eg, the Apnoea Hypopnoea Index (AHI)).[[9,19]] Our small sample size may be the reason for not finding statistically significant results, though a large proportion of individuals at high risk of tRHT were also at high risk of OSA. Thus in-depth studies with large sample sizes are needed to determine such associations or to confirm whether there is a correlation between sleep scores and BP parameters in adults with RHT.

Sociodemographic and anthropometric characteristics

We specifically recruited participants who were 60 years and younger, leading to a relatively young mean age for the cohort (51.8±8.9 years). The mean number of years treated for hypertension (5.2±2.2 years) indicated that some participants may have been in their 40s when such medication was first prescribed. Thus, RHT can occur at a relatively young age without being caused by factors such as chronic kidney disease and without the known risks for hypertension associated with older age.[[4]] The relatively low number of self-reported comorbidities (such as diabetes) may be due to the young age range of the sample. Such low prevalence of diabetes in RHT groups is in agreement with the results of a previous study that included a large cohort of patients with RHT.[[20]] Thus, diabetes may not be highly prevalent in younger groups with RHT. Although Māori have a higher risk of hypertension and higher use of antihypertensive medication than New Zealand Europeans,[[3]] the study sample included only a small number of Māori (n= 2). The low Māori representation (8%) could be due to Māori comprising only 8.7% of the Otago population (according to 2018 census data).[[23]] The small number of Māori participants may be due to advertisements not being accessible or sufficiently engaging for them. Our future studies will seek consultation and input from Māori stakeholder groups to improve the relevance of the study and enhance strategies to recruit Māori participants specifically. Previous studies over the past decade have reported a low prevalence of smoking in cohorts with RHT. [[18,20]] Our study had similar findings. Alcohol intake and coffee consumption reported by our sample also did not exceed the recommended limits.[[24]]

The high BMI (>30kg/m[[2]]) and increased neck (>40cm for male and >38cm for female) and waist (>94cm for male and >80cm for female )[[25]] circumferences indicate higher body fat and the presence of visceral and abdominal adiposity respectively in the group.[[25]] This is in agreement with previous studies with larger sample sizes and similar designs that have explored the anthropometrics of individuals with RHT.[[19,20]] The New Zealand Ministry of Health[[25]] has previously identified that increased BMI (>25kg/m[[2]]) and waist circumference (>80cm for male and >94cm for female) are risk factors for high BP and poor cardiovascular health.[[25]] The sample in the present research reported markedly higher values compared to the values recommended by the New Zealand Ministry of Health.[[25]] Excess adipose tissue has the potential to activate the renin angiotensin aldosterone system, increase sympathetic activity, promote insulin and leptin resistance and increase endothelial dysfunction.[[4]]

Blood pressure characteristics

The BP values were similar to values reported in previous studies with similar cohorts in which the average BP was in the range 145–165/80–90mmHg.[[19,20]] The study group at risk of tRHT can be categorised under the uncontrolled RHT category as described in a recent guideline.[[26]] This situation could lead to prescribing more medications to manage BP and could result in refractory hypertension.[[4]] Also it is important to note that the mean office BP of the present study sample was lower than the reported 24h ABP value, indicating the importance of confirming BP over a 24h period.

Sleep and activity characteristics

Both self-reported and objectively measured physical activity levels in the study group were above the recommended values for gaining health benefits as defined by the Eating and Activity Guidelines of Ministry of Health and other prominent guidelines.[[27]] Despite this, the BP of the group was high, even though they were using three or more antihypertensive medications. This suggests that the presently recommended physical activity levels (150–300 min per week of moderate to vigorous physical activities[[27,28]]) may not be sufficient to benefit the population with RHT. Thus, further investigations are warranted to determine the BP response to physical activity in people with RHT.

The present study indicated that low quality of life was associated with the condition RHT. This is in line with the small amount of literature that has been published previously.[[29,30]]

Strengths

To our knowledge this was the first time a New Zealand population with aRHT was included in a comprehensive investigation. Thus this study has provided a valuable dataset. We used the most recent American (AHA/ACC)[[1]] and New Zealand updated[[2]] guidelines for diagnostic values for hypertension to determine the prevalence. The selected study sample was aged below 60 and this minimised the independent influence of ageing and associated predisposing factors for RHT. This comprehensive study design with appropriately calculated sample sizes will be an important model to use in future studies in the field.

Limitations

The sample size was adapted in several ways to ensure the study was feasible within the constraints of the PhD timeframe. We were unable to recruit the required sample size, and therefore the conclusions are limited to this cohort and need to be considered with some caution. To diagnose tRHT, the condition in the definition “maximum or maximally tolerated dose” was not used due to practical difficulties. Thus, the exact prevalence of tRHT may vary from the reported proportions. We determined the OSA risk according to the sleep scores, and we did not use overnight polysomnography, which is the measure recommended for diagnosing OSA. As the sample may not have been fully representative of the entire New Zealand population, generalisability of our results cannot be assumed.

Recommendations

The prevalence of risk of OSA was high in this sample, confirming the need to screen for risk of OSA and assess sleep patterns in individuals diagnosed with, or at high risk of, tRHT. Lifestyle interventions, particularly exercise programmes and/or longer recommended periods of exercise than those for the general population, will be needed for this specific cohort at high risk of tRHT. Referring patients with RHT to health professionals, such as physiotherapists, for specific individualised exercise will also be beneficial upon confirmation of the positive outcomes of such interventions. To confirm the results of the present study, a country-based, large cohort study that addresses the reported limitations is highly recommended.

Conclusions

The prevalence of individuals at high risk of tRHT among aRHT was 88%, and the proportion at risk of OSA among the high-risk group for tRHT was 86%. The prevalence of tRHT may be high and OSA could be highly associated with RHT. The group was obese with higher neck and waist circumferences compared to recommended values, suggesting abdominal and visceral adiposity. Though the BP was high in the group, individuals were involved in levels of physical activity within the range recommended by the New Zealand Ministry of Health. However, the quality of life for this group was low, with the scores having been influenced by the reduced scores for the physical activity components of the questionnaire.

Summary

Abstract

Aim

To determine the prevalence of individuals at high risk of true resistant hypertension (tRHT) in Dunedin-based adults <60 years diagnosed with hypertension and pharmacologically managed with three or more antihypertensive medications (ie, apparent resistant hypertension (aRHT)); to describe characteristics of those with aRHT; and to investigate the association between tRHT and obstructive sleep apnoea in the group.

Method

Participants with aRHT were recruited and data collected using standardised equipment and methodology. Characteristics were reported using descriptive statistics. The proportion (with 95% confidence intervals) of individuals at high risk of tRHT in individuals with aRHT was calculated.

Results

Twenty-five aRHT individuals participated (17 males; group mean age 51.8±8.9 years; body mass index 33.6±6.2 kg/m^2). Measures (mean ±SD) for neck circumferences for males were 41.9±4.9cm, females 37.3±3.1cm; waist circumferences for males were 108.4±15.2cm, females 105.2±17.3cm. Group systolic and diastolic 24h ambulatory blood pressure (mmHg) were 148.9±20.5 (95% CI: 140.4 to 157.4), 88.2±14.6 (95% CI: 82.2 to 94.2); office blood pressure were 140.8±18.3 (95% CI: 133.2 to 148.3), 83.5±12.1 (95% CI: 78.5 to 88.5). The prevalence of individuals at high risk of tRHT was 88% (95% CI: 69% to 98%); proportion of obstructive sleep apnoea (OSA) risk among tRHT group was 86% (95% CI 65%to 97%).

Conclusion

The prevalence of individuals at high risk of both tRHT and OSA risk was large in Dunedin-based adults diagnosed with aRHT. Anthropometric assessments indicated high abdominal and visceral adiposity. Group mean blood pressure values exceeded New Zealand’s hypertension diagnostic value, suggesting uncontrolled RHT.

Author Information

Suranga Dassanayake: Assistant Research Fellow; Physiotherapist, Centre for Health, Activity and Rehabilitation Research, School of Physiotherapy, University of Otago, New Zealand. Gisela Sole: Assoc/Professor; Physiotherapist Centre for Health, Activity and Rehabilitation Research, School of Physiotherapy, University of Otago, New Zealand. Gerard Wilkins: Assoc/Professor; Cardiologist, Department of Medicine, Dunedin School of Medicine, University of Otago, New Zealand. Margot Skinner: Senior Lecturer; Physiotherapist Centre for Health, Activity and Rehabilitation Research, School of Physiotherapy, University of Otago, New Zealand.

Acknowledgements

Correspondence

Dr Margot Skinner, Centre for Health, Activity and Rehabilitation Research, School of Physiotherapy, University of Otago, PO Box 56, Dunedin 9054, New Zealand, +64 3 479 7466 (tel), +64 3 479 8414 (fax)

Correspondence Email

margot.skinner@otago.ac.nz

Competing Interests

Nil.

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