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Canadian Journal of Cardiology

Epidemiology of Resistant Hypertension in Canada

Open AccessPublished:February 02, 2022DOI:https://doi.org/10.1016/j.cjca.2022.01.029

      Abstract

      Background

      Resistant hypertension is associated with cardiovascular morbidity and mortality. The objective of this study was to estimate the prevalence of apparent treatment-resistant hypertension in Canadian adults and examine the characteristics of those affected.

      Methods

      A nationally representative cross-sectional study was conducted with the use of Canadian Health Measures Survey (2007-2017) data. The frequency of respondents with uncontrolled blood pressure despite 3 or more antihypertensive medications of different drug classes (and at least 1 agent being a diuretic), or treatment with 4 or more agents regardless of blood pressure, was determined.

      Results

      A total of 245,700 people were identified to have apparent treatment-resistant hypertension, representing 5.3% (95% confidence interval [CI] 4.5%–6.2%) of adults treated for hypertension in Canada. Respondents who had uncontrolled blood pressure with 3 or more antihypertensive drugs were more likely women (55.8%, 95% CI 41.1%-70.4%), 70 years of age or older (45.3% 95% CI 32.8%-57.9%), and overweight or obese (84.2%, 95% CI 72.3%-96.1%). Respondents with apparent treatment-resistant hypertension also had a high likelihood of chronic kidney disease (36.0%, 95% CI 21.4%-50.6%), diabetes (35.2%, 95% CI 21.7%-48.7%), dyslipidemia (68.0%, 95% CI 55.2%-80.8%), and history of heart attack (9.9%, 95% CI 4.8%-15.1%) or stroke (7.1%, 95% CI 0-14.4%).

      Conclusions

      Despite being prescribed at least 3 antihypertensive drugs, a considerable proportion of Canadians, especially women, have difficulty achieving blood pressure control, predisposing them to a higher risk of cardiovascular complications and death.

      Résumé

      Contexte

      L'hypertension résistante au traitement est associée à une morbidité et une mortalité cardiovasculaires. L'objectif de cette étude était d'estimer la prévalence de l'hypertension apparemment résistante au traitement chez les adultes canadiens et d'examiner les caractéristiques des personnes qui en étaient affectées.

      Méthodes

      Une étude transversale représentative, à l'échelle nationale, a été menée à l'aide des données de l'Enquête canadienne sur les mesures de la santé (2007-2017). On a déterminé la fréquence des participants dont la pression artérielle n'était pas maîtrisée malgré la prise de trois médicaments antihypertenseurs ou plus comprenant différentes classes de médicaments (dont au moins un agent étant un diurétique), ou le traitement avec quatre agents ou plus, quelle que soit la pression artérielle.

      Résultats

      Au total, 245 700 personnes ont été identifiées comme souffrant d'une hypertension apparemment résistante au traitement, ce qui représente 5,3 % (intervalle de confiance [IC] à 95 % : 4,5 %-6.2 %) des adultes traités pour hypertension au Canada. Les participants dont la pression artérielle n'était pas contrôlée par au moins trois médicaments antihypertenseurs étaient le plus souvent des femmes (55,8 %, IC à 95 % : 41,1 %-70,4 %), étaient âgés de 70 ans ou plus (45,3 %, IC à 95 % : 32,8 %-57,9 %) et présentant une surcharge pondérale ou une obésité (84,2 %, IC à 95 % : 72,3 %-96,1 %). Les participants présentant une hypertension apparemment résistante au traitement avaient également une forte probabilité de souffrir d'une maladie rénale chronique (36,0 %, IC à 95 % : 21,4 %-50,6 %), de diabète (35,2 %, IC à 95 % : 21,7 %-48,7 %), de dyslipidémie (68,0 %, IC à 95 % : 55,2 %-80,8 %) et d'antécédents de crise cardiaque (9,9 %, IC à 95 % : 4,8 %-15,1 %) ou d'accident vasculaire cérébral (7,1 %, IC à 95 % : 0-14,4 %).

      Conclusions

      Bien qu'au moins trois médicaments antihypertenseurs leur ait été prescrits, une proportion considérable de Canadiens, surtout des femmes, ont de la difficulté à contrôler leur pression artérielle, ce qui les prédispose à un risque plus élevé de complications cardiovasculaires et de décès.
      Blood pressure (BP) control is of enormous clinical and public health importance owing to the high prevalence of hypertension, detrimental consequences of uncontrolled BP, and proven benefits of reducing high BP in terms of lowering the risks of cardiovascular disease, kidney failure, and death.
      • Leung A.A.
      • Williams J.V.A.
      • McAlister F.A.
      • et al.
      Worsening hypertension awareness, treatment, and control rates in Canadian women between 2007 and 2017.
      ,
      • Ettehad D.
      • Emdin C.A.
      • Kiran A.
      • et al.
      Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis.
      Even so, there has been a growing care gap over the past decade in Canada, with BP control dropping from nearly 70% to less than 60% in recent years,
      • Leung A.A.
      • Williams J.V.A.
      • McAlister F.A.
      • et al.
      Worsening hypertension awareness, treatment, and control rates in Canadian women between 2007 and 2017.
      a finding associated with a corresponding rise in the rate of cardiovascular death since 2010.
      Institute for Health Metrics and Evaluation
      Global Burden of Disease Study. University of Washington.
      As such, a better understanding of the factors contributing to uncontrolled BP in Canada is urgently needed.
      • Feldman R.D.
      • Padwal R.S.
      • Tobe S.W.
      The rise and fall of hypertension control in Canada: the beginning of the end or the end of the beginning?.
      Patients who are treated yet remain uncontrolled represent an important segment of the population. Apparent treatment-resistant hypertension (aTRH) may be the result of inaccurate BP measurement, suboptimal medication regimens, medication nonadherence, or unrecognised secondary causes of hypertension, all of which may be potentially amenable to targeted interventions.
      • Burnier M.
      • Wuerzner G.
      • Struijker-Boudier H.
      • Urquhart J.
      Measuring, analyzing, and managing drug adherence in resistant hypertension.
      ,
      • Ruzicka M.
      • Leenen F.H.H.
      • Ramsay T.
      • et al.
      Use of directly observed therapy to assess treatment adherence in patients with apparent treatment-resistant hypertension.
      Compared with other forms of hypertension, the presence of aTRH is associated with an increased risk of cardiovascular morbidity and mortality, making identification of these individuals all the more important.
      • Muntner P.
      • Davis B.R.
      • Cushman W.C.
      • et al.
      Treatment-resistant hypertension and the incidence of cardiovascular disease and end-stage renal disease: results from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).
      • Irvin M.R.
      • Booth 3rd, J.N.
      • Shimbo D.
      • et al.
      Apparent treatment-resistant hypertension and risk for stroke, coronary heart disease, and all-cause mortality.
      • Daugherty S.L.
      • Powers J.D.
      • Magid D.J.
      • et al.
      Incidence and prognosis of resistant hypertension in hypertensive patients.
      Accordingly, it is critical to understand the characteristics of Canadians who have difficult-to-control hypertension so that targeted interventions can be provided to improve BP control in this important subgroup to reduce sequelae. Addressing this, we used the Canadian Health Measures Survey (CHMS) to estimate the prevalence of aTRH among Canadian adults aged 20 to 79 years, and examined the characteristics of those affected in order to determine who may potentially benefit from specialised diagnostic workup, specific treatments, or targeted interventions.

      Methods

      Data source

      The CHMS is an ongoing cross-sectional survey designed to provide nationally representative estimates of common medical conditions by means of complex stratified sampling.
      • Giroux S.
      Canadian Health Measures Survey: sampling strategy overview.
      ,
      • Tremblay M.
      • Wolfson M.
      • Connor Gorber S.
      Canadian Health Measures Survey: rationale, background and overview.
      The sampling frame covers more than 96% of the Canadian population (excluding full-time members of the Canadian Armed Forces, persons living on reserves or other aboriginal settlements, the institutionalised, and those living in some remote regions of Canada).
      • Giroux S.
      Canadian Health Measures Survey: sampling strategy overview.
      Sociodemographic and health information data were collected through in-person household interviews, followed by visits to mobile examination centers for direct physical measures.
      • Tremblay M.
      • Wolfson M.
      • Connor Gorber S.
      Canadian Health Measures Survey: rationale, background and overview.
      ,
      • Bryan S.
      • St-Denis M.
      • Wojtas D.
      Canadian Health Measures Survey: clinic operations and logistics.
      Data for this study were from the first (2007-2009), second (2009-2011), third (2012-2013), fourth (2014-2015), and fifth (2016-2017) cycles of the CHMS.
      Statistics Canada
      Canadian Health Measures Survey (CHMS) data user guide: cycle 1 April 2011.
      Statistics Canada
      Canadian Health Measures Survey (CHMS) data user guide: cycle 2 November 2012.
      Statistics Canada
      Canadian Health Measures Survey (CHMS) data user guide: cycle 3 November 2014.
      Statistics Canada
      Canadian Health Measures Survey (CHMS) data user guide: cycle 4 December 2016.
      Statistics Canada
      Canadian Health Measures Survey (CHMS) data user guide: cycle 5 October 2018.
      The response rates for the cycles 1 to 5 were, respectively, 51.7%, 55.5%, 51.7%, 53.7%, and 48.5%. The resulting analytic sample size was 16,602 for adults aged 20 to 79 years.

      Measures and definitions

      Hypertension

      Respondents were considered to be hypertensive if their mean systolic blood pressure (SBP) was ≥ 140 mm Hg or diastolic blood pressure (DBP) was ≥ 90 mm Hg, or if they reported taking an antihypertensive medication in the past month.
      • Leung A.A.
      • Williams J.V.A.
      • McAlister F.A.
      • et al.
      Worsening hypertension awareness, treatment, and control rates in Canadian women between 2007 and 2017.
      ,
      • Leung A.A.
      • Bushnik T.
      • Hennessy D.
      • McAlister F.A.
      • Manuel D.G.
      Risk factors for hypertension in Canada.
      • Padwal R.S.
      • Bienek A.
      • McAlister F.A.
      • Campbell N.R.
      Epidemiology of hypertension in Canada: an update.
      NCD. Risk Factor Collaboration
      Long-term and recent trends in hypertension awareness, treatment, and control in 12 high-income countries: an analysis of 123 nationally representative surveys.
      Among those with hypertension, individuals who reported using an antihypertensive medication in the past month were defined as treated, and those with a mean SBP < 140 mm Hg and DBP < 90 mm Hg were classified as controlled. Respondents with uncontrolled BP despite reporting the use of 3 or more antihypertensive medications of different drug classes (and at least 1 of them being a diuretic), or those treated with 4 or more agents regardless of BP, were defined as having aTRH, to be as consistent as possible with other studies.
      • Carey R.M.
      • Calhoun D.A.
      • Bakris G.L.
      • et al.
      Resistant hypertension: detection, evaluation, and management: a scientific statement from the American Heart Association.
      We also used the preferred term aTRH (“apparent treatment-resistant hypertension”) rather than “resistant hypertension” because the possibility of treatment nonadherence could not be ruled out, as medication use was self-reported and adherence was not verified through assessment of pharmacologic concentrations and/or directly observed therapy.

      Blood pressure

      BP was measured by means of an automated office BP method using calibrated BpTRU BPM-200 and BPM-300 oscillometric devices (BpTRU Medical Devices, Coquitlam, BC).
      • Bryan S.
      • Saint-Pierre Larose M.
      • Campbell N.
      • Clarke J.
      • Tremblay M.S.
      Resting blood pressure and heart rate measurement in the Canadian Health Measures Survey, cycle 1.
      ,
      • Nerenberg K.A.
      • Zarnke K.B.
      • Leung A.A.
      • et al.
      Hypertension Canada’s 2018 guidelines for diagnosis, risk assessment, prevention, and treatment of hypertension in adults and children.
      After 5 minutes of rest, 6 sequential measurements at 1-minute intervals were taken while unattended. The last 5 readings were then used to calculate the mean SBP and DBP for each person.
      • Bryan S.
      • Saint-Pierre Larose M.
      • Campbell N.
      • Clarke J.
      • Tremblay M.S.
      Resting blood pressure and heart rate measurement in the Canadian Health Measures Survey, cycle 1.

      Medications

      Antihypertensive medications were classified into drug classes according to their Anatomical Therapeutic Chemical (ATC) codes (Supplemental Table S1).
      • Leung A.A.
      • Williams J.V.A.
      • McAlister F.A.
      • et al.
      Worsening hypertension awareness, treatment, and control rates in Canadian women between 2007 and 2017.
      ,
      • Leung A.A.
      • Bushnik T.
      • Hennessy D.
      • McAlister F.A.
      • Manuel D.G.
      Risk factors for hypertension in Canada.
      ,
      • Bushnik T.
      • Hennessy D.A.
      • McAlister F.A.
      • Manuel D.G.
      Factors associated with hypertension control among older Canadians.
      Analysis was based on these discrete classes, but the final reporting was aggregated according to broader categories (eg, angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers were collectively grouped into “renin-angiotensin system inhibitors”).

      Other factors

      Diabetes was defined by self-report, a glycated hemoglobin A1c of 6.5% or higher, or the use of a glucose-lowering medication (ATC code A10). Chronic kidney disease was based on a glomerular filtration rate less than 60 mL/min/1.73 m2, estimated with the use of the 4-variable Modification of Diet in Renal Disease equation.
      • Coresh J.
      • Selvin E.
      • Stevens L.A.
      • et al.
      Prevalence of chronic kidney disease in the United States.
      Participants who had a body mass index of 25.0 kg/m2 or more were classified as overweight or obese. Personal history of dyslipidemia, heart attack, stroke, smoking, usual physical activity, and typical consumption of fruit and vegetables were based on self-report. Family history of high BP or early cardiovascular disease (ie, heart disease or stroke before the age of 60 years) was also based on self-report.

      Statistical analysis

      Data from all available cycles of the CHMS were pooled by applying respondent-specific survey weights to generate population-representative estimates, and variances were determined with the use of bootstrapping to account for the complex survey design.
      Statistics Canada
      Canadian Health Measures Survey (CHMS) data user guide: cycle 1 April 2011.
      Statistics Canada
      Canadian Health Measures Survey (CHMS) data user guide: cycle 2 November 2012.
      Statistics Canada
      Canadian Health Measures Survey (CHMS) data user guide: cycle 3 November 2014.
      ,
      Statistics Canada
      Instructions for combining multiple cycles of Canadian Health Measures Survey (CHMS) data 2017.
      The proportion of respondents with aTRH was calculated and descriptive statistics of their characteristics reported. In adherence with Statistics Canada’s policy, absolute numbers were rounded to the nearest 100, and estimates based on sample sizes of fewer than 5 respondents were suppressed. These cases were handled either by omitting the corresponding cells or by combining multiple subgroups together to satisfy the requirements for data release and publication. We conducted 2 sensitivity analyses to facilitate comparisons
      • Leung A.A.
      • Williams J.V.A.
      • McAlister F.A.
      • et al.
      Worsening hypertension awareness, treatment, and control rates in Canadian women between 2007 and 2017.
      ,
      • Leung A.A.
      • Bushnik T.
      • Hennessy D.
      • McAlister F.A.
      • Manuel D.G.
      Risk factors for hypertension in Canada.
      ,
      • Padwal R.S.
      • Bienek A.
      • McAlister F.A.
      • Campbell N.R.
      Epidemiology of hypertension in Canada: an update.
      : first, recognising that BpTRU SBP and DBP measurements may be slightly lower than conventional manual BP readings,
      • Myers M.G.
      • McInnis N.H.
      • Fodor G.J.
      • Leenen F.H.
      Comparison between an automated and manual sphygmomanometer in a population survey.
      we applied a validated correction
      • Myers M.G.
      • McInnis N.H.
      • Fodor G.J.
      • Leenen F.H.
      Comparison between an automated and manual sphygmomanometer in a population survey.
      and used the adjusted values to determine the prevalence of hypertension and aTRH (defined by a mean SBP of ≥ 140 mm Hg or DBP of ≥ 90 mm Hg); second, we examined the proportion of people with hypertension and aTRH according to the BP threshold provided by the American College of Cardiology and American Heart Association guidelines (a mean SBP of ≥ 130 mm Hg or DBP of ≥ 80 mm Hg based on unadjusted BpTRU measurements).
      • Whelton P.K.
      • Carey R.M.
      • Aronow W.S.
      • et al.
      2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the 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.
      We then assessed for predictors for aTRH among those who were treated for hypertension. Potential risk factors were selected a priori based on clinical reasoning and previous reports.
      • Egan B.M.
      • Zhao Y.
      • Axon R.N.
      • Brzezinski W.A.
      • Ferdinand K.C.
      Uncontrolled and apparent treatment resistant hypertension in the United States 1988 to 2008.
      Logistic regression modelling was used to estimate risk ratios (RRs), adjusting for other covariates, and stratified according to sex. The candidate variables were all dichotomous, except age, which was modelled as a multicategoric variable (with age bands corresponding to 20-59, 60-69, and 70-79 years) to allow for the possibility of nonlinear associations. All statistical analyses were performed using Stata 16.0 (StataCorp, College Station, TX).

      Results

      There was a total of 26,041,200 Canadian adults represented in the survey (rounded to the nearest 100) and 5,820,400 of them had hypertension (23.2%, 95% CI 22.1%-24.4%). Of these, 79.1% (95% CI 76.4%-81.8%) were treated with at least 1 antihypertensive drug. Treated patients had a mean SBP and DBP of 122.9 and 73.7 mm Hg, respectively, and they were taking an average of 1.8 antihypertensive medications in the past month (Table 1). The mean age of treated individuals was 61.7 years, approximately half were men, and the majority were white. Being overweight or obese, engaging in less than 150 minutes of moderate to vigorous physical activity per week, and consuming fruits and vegetables less than 5 times per day were common: present in more than 80% of those treated. More than half had dyslipidemia, nearly one-third had diabetes, and more than 1 in 10 had chronic kidney disease.
      Table 1Characteristics of Canadian adults, aged 20 to 79 years, with hypertension
      CharacteristicsHypertensionApparent treatment-resistant hypertension
      AllTreatedAllUncontrolled with ≥ 3 medicationsTaking ≥ 4 medications
      No. represented, rounded to nearest 1005,820,4004,605,400245,700109,750135,950
      Proportion among those treated, %1005.3 (4.5-6.2)2.4 (1.7-3.1)3.0 (2.3-3.6)
      Baseline sociodemographics
       Age, years60.4 (59.9-60.9)61.7 (61.1-62.4)67.5 (65.5-69.5)66.8 (64.5-69.1)68.1 (64.8-71.4)
      Age category, %
       20-59 y43.1 (40.7-45.5)37.9 (35.0-40.8)18.1 (9.5-26.7)18.3 (4.5-32.1)17.9 (5.4-30.3)
       60-69 y33.8 (31.7-35.9)36.4 (34.0-38.9)31.8 (23.4-40.2)36.3 (23.8-48.9)28.2 (15.8-40.6)
       70-79 y23.1 (21.3-24.9)25.7 (23.7-27.7)50.1 (40.8-59.3)45.3 (32.8-57.9)53.9 (39.9-67.9)
       Men, %53.1 (50.7-55.4)53.3 (50.6-55.9)58.1 (46.6-69.5)44.2 (29.6-58.9)69.3 (54.3-84.2)
       White race, %84.9 (80.3-89.5)85.2 (80.3-90.2)89.3 (81.3-97.2)90.6 (80.6-100)88.2 (76.5-99.9)
      Marital status, %
       Married or common-law71.7 (68.9-74.6)72.9 (70.1-75.7)68.9 (61.3-76.4)73.1 (61.8-84.4)65.5 (53.9-77.0)
       Other (single, widowed, separated, or divorced)28.3 (25.4-31.1)27.1 (24.3-29.9)31.1 (23.6-38.6)26.9 (15.6-38.2)34.5 (23.0-46.1)
       Less than secondary school graduation, %41.9 (39.4-44.5)43.3 (40.3-46.4)44.1 (34.2-54.1)45.4 (31.3-59.6)43.1 (30.8-55.5)
      Anthropometrics
       Overweight or obese, %80.5 (77.7-83.3)82.6 (79.9-85.2)90.7 (85.0-96.3)84.2 (72.3-96.1)95.9 (92.3-99.5)
       Systolic blood pressure, mm Hg127.6 (126.6-128.7)122.9 (122.0-123.8)132.6 (128.1-137.2)150.8 (147.3-154.2)118.0 (113.7-122.3)
       Diastolic blood pressure, mm Hg76.9 (76.3-77.6)73.7 (73.1-74.4)71.8 (69.5-74.1)79.1 (76.2-82.0)65.8 (63.5-68.2)
       Heart rate, beats/min67.6 (66.9-68.4)66.9 (66.1-67.6)63.2 (60.9-65.5)64.9 (61.9-67.9)61.9 (58.7-65.1)
      Medications
       No. of antihypertensive medications taken in the past month1.4 (1.4-1.5)1.8 (1.7-1.8)3.8 (3.6-4.0)3.5 (3.3-3.8)4.0 (3.8-4.3)
      Antihypertensive medications by drug class, %
       Beta-blockers20.9 (19.1-22.7)24.6 (22.6-26.6)69.3 (60.2-78.3)57.4 (44.0-70.9)78.8 (65.1-92.5)
       Renin-angiotensin system inhibitors65.3 (63.1-67.6)75.3 (73.1-77.5)98.4 (96.7-100.0)NR
      Not reported due to small cell sizes (eg, nearly all respondents with treatment-resistant hypertension were taking a renin-angiotensin system inhibitor, and therefore very few people were not prescribed a medication from this drug class).
      NR
      Not reported due to small cell sizes (eg, nearly all respondents with treatment-resistant hypertension were taking a renin-angiotensin system inhibitor, and therefore very few people were not prescribed a medication from this drug class).
       Diuretics35.7 (33.2-38.1)42.0 (39.6-44.5)90.7 (84.3-97.2)100
      Use of thiazide/thiazide-like diuretics was part of the definition (ie, uncontrolled blood pressure despite ≥ 3 drugs and at least 1 of them being a diuretic).
      83.2 (72.7-93.8)
       Potassium-sparing diuretics3.1 (2.4-3.8)3.7 (2.8-4.5)7.1 (3.4-10.8)8.0 (1.2-14.7)6.4 (1.9-10.8)
       Calcium channel blockers21.9 (20.1-23.7)25.8 (23.7-27.9)72.6 (63.1-82.2)54.6 (39.0-70.1)87.2 (78.1-96.4)
       Other antihypertensive drugs7.0 (5.8-8.3)8.9 (7.3-10.4)37.8 (27.2-48.5)10.5 (3.5-17.5)59.9 (47.1-72.7)
      Comorbidities, %
       Chronic kidney disease13.1 (11.7-14.6)15.5 (13.7-17.4)31.6 (23.2-40.0)36.0 (21.4-50.6)28.1 (18.5-37.7)
       Diabetes24.2 (22.3-26.1)28.8 (26.5-31.0)46.7 (35.3-58.0)35.2 (21.7-48.7)55.9 (43.1-68.8)
       Dyslipidemia52.2 (49.8-54.6)59.6 (57.0-62.3)79.4 (73.0-85.8)68.0 (55.2-80.8)88.6 (84.1-93.0)
       Heart attack8.8 (7.6-10.1)11.0 (9.4-12.6)22.8 (14.2-31.4)9.9 (4.8-15.1)33.1 (18.8-47.4)
       Stroke2.5 (1.9-3.1)3.1 (2.4-3.9)5.8 (2.2-9.3)7.1 (0-14.4)4.7 (0.4-8.9)
      Family history, %
       High blood pressure61.0 (58.7-63.4)62.7 (60.2-65.2)73.1 (64.5-81.7)69.9 (54.1-85.6)75.8 (67.8-84.0)
       Early cardiovascular disease45.6 (42.5-48.8)46.5 (43.2-49.8)62.0 (49.6-74.5)64.4 (45.0-83.8)60.1 (42.8-77.5)
      Other factors, %
       Active smoking16.1 (14.3-17.8)15.3 (13.4-17.2)18.4 (9.9-26.9)11.6 (1.2-22.0)23.8 (10.7-37.0)
       < 150 min moderate to vigorous physical activity per week
      Physical activity was available only for cycles 3, 4, and 5.
      81.4 (78.4-84.4)81.9 (78.7-85.0)88.9 (84.5-93.4)NR
      Not reported due to small cell sizes (eg, nearly all respondents with treatment-resistant hypertension were taking a renin-angiotensin system inhibitor, and therefore very few people were not prescribed a medication from this drug class).
      NR
      Not reported due to small cell sizes (eg, nearly all respondents with treatment-resistant hypertension were taking a renin-angiotensin system inhibitor, and therefore very few people were not prescribed a medication from this drug class).
       Fruit and vegetable consumption < 5 times per day87.0 (85.4-88.7)87.0 (85.4-88.7)88.0 (83.4-92.6)87.2 (80.5-93.9)88.7 (83.4-94.0)
       Regular medical doctor92.6 (91.1-94.0)95.5 (94.1-96.9)94.3 (90.5-98.1)95.8 (91.3-100.0)93.1 (86.6-99.6)
      Framingham risk score for 10-year risk of cardiovascular disease,
      Framingham risk score was not calculated for individuals with known cardiovascular disease.
      %
       ≤ 19%65.7 (63.7-67.6)62.9 (60.6-65.1)33.8 (22.3-45.3)24.2 (10.6-37.7)43.9 (23.2-64.6)
       ≥ 20%34.3 (32.4-36.3)37.1 (34.9-39.4)66.2 (54.7-77.7)75.8 (62.3-89.4)56.1 (35.4-76.8)
      Ranges in parentheses are 95% confidence intervals. Percentages, means, and confidence intervals based on weighted estimates.
      Not reported due to small cell sizes (eg, nearly all respondents with treatment-resistant hypertension were taking a renin-angiotensin system inhibitor, and therefore very few people were not prescribed a medication from this drug class).
      Use of thiazide/thiazide-like diuretics was part of the definition (ie, uncontrolled blood pressure despite ≥ 3 drugs and at least 1 of them being a diuretic).
      Physical activity was available only for cycles 3, 4, and 5.
      § Framingham risk score was not calculated for individuals with known cardiovascular disease.
      Overall, aTRH was present in 245,700 of the sample, representing 5.3% (95% CI 4.5%-6.2%) of adults who were treated for hypertension in Canada, and the prevalence was similar in each cycle of the survey (Table 2). Slightly less than half of these people with aTRH had uncontrolled BP even though they reported taking at least 3 antihypertensive medications, while the remainder were taking at least 4 antihypertensive medications in the past month. In our sensitivity analyses, the prevalence of aTRH and its individual components were broadly similar after adjusting for possible differences in measurements obtained using automatic oscillometric devices vs traditional manual BP measurements, as well as when a threshold of 130/80 mm Hg for high BP was applied (Supplemental Table S2).
      Table 2Prevalence of apparent treatment-resistant hypertension
      CycleYearsTotal no.Uncontrolled BP with ≥ 3 medications, %Taking ≥ 4 medications, %Apparent treatment-resistant hypertension, %
      12007-200943,7003.3 (2.0-4.6)2.3 (1.5-3.0)5.6 (4.3-6.8)
      22009-201176,5002.7 (0.5-5.0)4.6 (2.5-6.8)7.3 (4.3-10.3)
      32012-201340,4002.4 (0.8-4.0)1.8 (0.2-3.3)4.2 (2.7-5.7)
      42014-201546,6502.0 (1.0-3.0)2.9 (1.8-4.1)4.9 (3.3-6.5)
      52016-201738,4501.6 (0.6-2.5)2.9 (1.9-3.9)4.5 (3.3-5.7)
      All2007-2017245,7002.4 (1.7-3.1)3.0 (2.3-3.6)5.3 (4.5-6.2)
      The denominator is number of people with treated hypertension. Note that people with uncontrolled blood pressure (BP) despite taking 3 or more medications and those taking 4 or more medications are not mutually exclusive, and there may occasionally be small numbers of people that overlap. Therefore, the sum of the 2 categories does not necessarily equal the final percentage of people with apparent treatment-resistant hypertension.
      Adults with aTRH had mean SBP and DBP of 132.6 and 71.8 mm Hg, respectively (Table 1). Those who had uncontrolled BP despite taking 3 or more antihypertensive drugs had mean SBP and DBP of 150.8 and 79.1 mm Hg, and those who were taking 4 or more antihypertensive drugs (regardless of BP) had mean SBP and DBP of 118.0 and 65.8 mm Hg, respectively. Nearly all respondents were taking diuretics and renin-angiotensin system inhibitors in the past month, and more than a third were also taking beta-blockers and calcium channel blockers. Respondents with aTRH were typically older and more commonly men compared with those with treated hypertension in general. Being overweight or obese and engaging in less than 150 minutes of moderate to vigorous physical activity per week were nearly 10% more frequent in those with aTRH. Respondents with aTRH, compared with those with treated hypertension in general, were twice as likely to have diabetes, chronic kidney disease, heart attack, stroke, or a family history of high blood pressure or premature cardiovascular disease. In contrast to most patients with hypertension (where the risk of incident cardiovascular disease was estimated to be low to moderate), two-thirds of those with aTRH were at high cardiovascular risk based on the Framingham risk score.
      There were notable differences between respondents with uncontrolled BP despite taking 3 or more antihypertensive drugs vs those taking 4 or more drugs regardless of BP achieved. The former were more commonly women (55.8% vs 30.7%), were less likely to be overweight or obese (84.2% vs 95.9%), and were more likely to have chronic kidney disease (36.0% vs 28.1) and stroke (7.1% vs 4.7%), but had considerably lower prevalence of diabetes (35.2% vs 55.9%), dyslipidemia (68.0% vs 88.6%), and heart attack (9.9% vs 33.1%). While there were high levels of use of every major antihypertensive drug class (including renin-angiotensin system inhibitors, diuretics, calcium channel blockers, and beta-blockers), the use of antihypertensive drugs from other categories was considerably less common among respondents who had uncontrolled BP on 3 or more drugs vs those who were taking 4 or more drugs (10.5% vs 59.9%).
      After covariate adjustment, 4 risk factors were significantly associated with aTRH in adult men (Supplemental Table S3): age from 70 to 79 years (compared with men aged 20 to 59 years: RR 5.0, 95% CI 1.6-16.2), being overweight or obese (RR 2.5, 95% CI 1.1-5.9), chronic kidney disease (RR 1.9, 95% CI 1.1-3.2), and diabetes (RR 2.5, 95% CI 1.5-4.4). Among adult women, age from 70 to 79 years was the only statistically significant predictor of aTRH (RR 2.7, 95% CI 1.1-6.7). Similarly to men, however, women with chronic kidney disease and diabetes appeared to be at a 2-fold higher risk of aTRH, but these latter associations were not statistically significant.

      Discussion

      In this study, aTRH was present 1 in 20 adults treated for high BP (representing nearly a quarter million people) in Canada; aTRH occurred most frequently in the elderly and commonly coexisted with being overweight or obese, having diabetes, and the presence of chronic kidney disease. Affected adults were at very high cardiovascular risk, with one-fourth reporting a history of heart attack and more than 1 in 20 having suffered a stroke. Those with uncontrolled BP despite the use of 3 or more antihypertensive drugs were more often women, a finding consistent with known sex disparities in the treatment and control of hypertension in Canada.
      • Leung A.A.
      • Williams J.V.A.
      • McAlister F.A.
      • et al.
      Worsening hypertension awareness, treatment, and control rates in Canadian women between 2007 and 2017.
      ,
      • Bushnik T.
      • Hennessy D.A.
      • McAlister F.A.
      • Manuel D.G.
      Factors associated with hypertension control among older Canadians.
      ,
      • Gee M.E.
      • Bienek A.
      • McAlister F.A.
      • et al.
      Factors associated with lack of awareness and uncontrolled high blood pressure among Canadian adults with hypertension.
      The findings of our study extend those of previous reports. The true prevalence of resistant hypertension around the world remains uncertain, owing to large differences in disease definitions, BP measurement techniques, and populations between studies.
      • Noubiap J.J.
      • Nansseu J.R.
      • Nyaga U.F.
      • et al.
      Global prevalence of resistant hypertension: a meta-analysis of data from 3.2 million patients.
      In a recent systematic review and meta-analysis, Noubiap et al. estimated that resistant hypertension was present in approximately 10% of patients treated for high BP globally (ranging from 1.2% to 25.5%), but there was a large amount of unexplained statistical heterogeneity between studies, even when restricted to those of highest quality and lowest risk of bias (I2 = 94.4%), thus limiting the interpretability of the pooled prevalence.
      • Noubiap J.J.
      • Nansseu J.R.
      • Nyaga U.F.
      • et al.
      Global prevalence of resistant hypertension: a meta-analysis of data from 3.2 million patients.
      In contrast to our study, where we used an unattended automated office BP measurement, many previous studies measured BP by auscultation without an out-of-office component, which likely accounted for the higher rates of aTRH in other studies. Previous Canadian-specific estimates were reported by Gee et al., dating back over a decade, placing the prevalence of aTRH at 4% to 8% among hypertensive adults.
      • Gee M.E.
      • Bienek A.
      • McAlister F.A.
      • et al.
      Factors associated with lack of awareness and uncontrolled high blood pressure among Canadian adults with hypertension.
      The consistency of their findings with ours is expected because they also used the CHMS as their data source (ie, cycle 1), but they were limited by small sample size (of fewer than 1000 people) and therefore could not provide detailed characteristics about those affected. In contrast, we found that the majority of Canadians with uncontrolled BP with 3 or more medications were women and nearly half were aged 70 years or older. Our findings bear similarities with other Western countries. Reports from the National Health and Nutrition Examination Survey have also indicated that American women aged 75 years or older have the lowest rates of general hypertension treatment and control (at 43% and 34%, respectively),
      • Kovell L.C.
      • Harrington C.M.
      • Michos E.D.
      Update on blood pressure control among US adults with hypertension.
      ,
      • Muntner P.
      • Hardy S.T.
      Update on blood pressure control among US adults with hypertension—reply.
      with women representing more than 60% of people with uncontrolled hypertension taking 3 or more medications in the United States.
      • Egan B.M.
      • Zhao Y.
      • Axon R.N.
      • Brzezinski W.A.
      • Ferdinand K.C.
      Uncontrolled and apparent treatment resistant hypertension in the United States 1988 to 2008.
      While the prevalence of aTRH also increases with age in the United Kingdom, no major sex differences have been observed,
      • Sinnott S.J.
      • Smeeth L.
      • Williamson E.
      • Douglas I.J.
      Trends for prevalence and incidence of resistant hypertension: population based cohort study in the UK 1995-2015.
      suggesting that differences in North America may be at least partly driven by social determinants of health, organisations of care, underrecognition, and/or therapeutic inertia.
      The factors underlying aTRH are complex and multifactorial. Medication nonadherence, inaccurate BP measurement, suboptimal treatment regimens, and unrecognised secondary causes of hypertension are among the leading causes.
      • Carey R.M.
      • Calhoun D.A.
      • Bakris G.L.
      • et al.
      Resistant hypertension: detection, evaluation, and management: a scientific statement from the American Heart Association.
      ,
      • Garg J.P.
      • Elliott W.J.
      • Folker A.
      • et al.
      Resistant hypertension revisited: a comparison of two university-based cohorts.
      Indeed, medication nonadherence is thought to be present in a third of cases (with rates as high as 50% when chemical tests are used to verify drug exposure).
      • Durand H.
      • Hayes P.
      • Morrissey E.C.
      • et al.
      Medication adherence among patients with apparent treatment-resistant hypertension: systematic review and meta-analysis.
      Possible strategies to improve adherence include the adoption of simplified medication regimens (eg, single-pill fixed-dose combinations of antihypertensive drugs), preferential use of generic or low-cost drugs, and enhanced communication with patients about potential adverse effects and benefits of treatment.
      • Carey R.M.
      • Calhoun D.A.
      • Bakris G.L.
      • et al.
      Resistant hypertension: detection, evaluation, and management: a scientific statement from the American Heart Association.
      Furthermore, undertreatment (eg, inadequate medication dosing) and underrecognition of secondary causes are other important factors leading to apparent treatment resistance.
      • Garg J.P.
      • Elliott W.J.
      • Folker A.
      • et al.
      Resistant hypertension revisited: a comparison of two university-based cohorts.
      Addressing these, adoption of standardised treatment algorithms (eg, guidance for specific drugs, doses, and titration schedules)
      • Fontil V.
      • Gupta R.
      • Moise N.
      • et al.
      Adapting and evaluating a health system intervention from Kaiser Permanente to improve hypertension management and control in a large network of safety-net clinics.
      and promotion of healthy behaviours (eg, dietary sodium reduction in those who are salt sensitive, working toward a healthy weight in those who are overweight or obese)
      • Blumenthal J.A.
      • Hinderliter A.L.
      • Smith P.J.
      • et al.
      Effects of lifestyle modification on patients with resistant hypertension: results of the TRIUMPH randomized clinical trial.
      have proven to be effective at improving BP control. Moreover, given that resistant hypertension is often volume mediated,
      • Gaddam K.K.
      • Nishizaka M.K.
      • Pratt-Ubunama M.N.
      • et al.
      Characterization of resistant hypertension: association between resistant hypertension, aldosterone, and persistent intravascular volume expansion.
      ,
      • Brown J.M.
      • Siddiqui M.
      • Calhoun D.A.
      • et al.
      The unrecognized prevalence of primary aldosteronism: a cross-sectional study.
      the use of potassium-sparing diuretics (eg, spironolactone) is increasingly recognised to have a central role in treatment,
      • Williams B.
      • MacDonald T.M.
      • Morant S.
      • et al.
      Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial.
      but few Canadians with aTRH (7%) reported taking these (with similarly low rates in the U.S.).
      • Cohen J.B.
      • Cohen D.L.
      • Herman D.S.
      • et al.
      Testing for primary aldosteronism and mineralocorticoid receptor antagonist use among U.S. veterans: a retrospective cohort study.
      Collectively, these interventions could potentially improve the health of hundreds of thousands of Canadians.

      Study limitations

      While there are many strengths to this study (eg, it was comprehensive and used high-quality data with blood pressure measurements collected by means of a standardised automated technique), there are also some limitations. First, inherent to all surveys, if nonrespondents were systematically different than those who participated, unknown bias may have been introduced. Addressing this, we applied survey weights so that respondents would be representative of the underlying population of interest according to sociodemographic characteristics (eg, age and gender), but it was not possible to ensure that their clinical characteristics (eg, BP and medication usage) were also similar. Second, treatment exposure was based entirely on self-report. We were unable to account for treatment nonadherence by patients (eg, missed doses) or undertreatment by physicians (eg, inadequate dosing or selection of medication combinations that are less likely to be effective). As such, we could not report on rates of resistant hypertension, but only aTRH. Third, we could not confirm the primary indication for taking an antihypertensive drug (ie, whether it was prescribed for high BP or for another condition, such as heart failure). Therefore, our estimated treatment rates may have been subject to some degree of misclassification, though this likely would have been small.
      • Wilkins K.
      • Gee M.
      • Campbell N.
      The difference in hypertension control between older men and women.
      Fourth, we could not completely rule out misclassification from a single visit office-based BP measurement. Still, unattended automated office BP measurements are thought to largely mitigate the white-coat effect,
      • Myers M.G.
      • McInnis N.H.
      • Fodor G.J.
      • Leenen F.H.
      Comparison between an automated and manual sphygmomanometer in a population survey.
      ,
      • Roerecke M.
      • Kaczorowski J.
      • Myers M.G.
      Comparing automated office blood pressure readings with other methods of blood pressure measurement for identifying patients with possible hypertension: a systematic review and meta-analysis.
      and compared with the criterion standard of 24-hour ambulatory blood pressure measurements, they have high specificity (81%-91%) for detecting elevated BP.
      • Viera A.J.
      • Yano Y.
      • Lin F.C.
      • et al.
      Does this adult patient have hypertension? The rational clinical examination systematic review.
      Fifth, we did not factor more intensive treatment goals for certain groups (eg, BP < 130/80 mm Hg in people with diabetes, or SBP < 120 mm Hg in high-risk adults),
      • Rabi D.M.
      • McBrien K.A.
      • Sapir-Pichhadze R.
      • et al.
      Hypertension Canada’s 2020 Comprehensive guidelines for the prevention, diagnosis, risk assessment, and treatment of hypertension in adults and children.
      but rather assumed a common BP target for all respondents because treatment decisions are frequently nuanced. Applying a lower BP target would doubtlessly have raised the prevalence of aTRH, which may have been one of the reasons why our estimates were slightly lower than others.
      • Gee M.E.
      • Bienek A.
      • McAlister F.A.
      • et al.
      Factors associated with lack of awareness and uncontrolled high blood pressure among Canadian adults with hypertension.
      ,
      • Noubiap J.J.
      • Nansseu J.R.
      • Nyaga U.F.
      • et al.
      Global prevalence of resistant hypertension: a meta-analysis of data from 3.2 million patients.
      Finally, we identified a number of risk factors associated with aTRH, but causal relationships could not be established because data were cross-sectional. Further study is needed to determine if treatment of modifiable risk factors leads to improved long-term BP control.
      • Blumenthal J.A.
      • Hinderliter A.L.
      • Smith P.J.
      • et al.
      Effects of lifestyle modification on patients with resistant hypertension: results of the TRIUMPH randomized clinical trial.

      Conclusion

      Apparent treatment-resistant hypertension is associated with a significantly higher frequency of cardiovascular disease compared with treatment-responsive hypertension. Despite being prescribed multiple BP-lowering medications, a considerable proportion of Canadians, especially women, have difficulty achieving long-term BP control, thus predisposing them to a greater risk of cardiovascular complications and death. Strategies to effectively control BP in high-risk populations, such as the elderly, people who are overweight or obese, and those with chronic kidney disease or diabetes, as well as to narrow sex-based care gaps are urgently needed.

      Funding Sources

      This study was funded by the Canadian Institutes of Health Research (project grant no 159533). Dr Leung is supported by a Heart and Stroke Foundation National New Investigator Award.

      Disclosures

      Dr Padwal is CEO of mmHg Inc, a digital health company that creates cloud-based solutions for remote patient monitoring and management. The other authors have no conflicts of interest to disclose.

      Supplementary Material

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      Linked Article

      • Identifying Resistant Hypertension in the Population: The Devil Is in the Details
        Canadian Journal of CardiologyVol. 38Issue 5
        • Preview
          A critical factor in assessing rates of prevalence in a population is robust local surveillance data. Estimating the prevalence of resistant hypertension has proven to be a challenging research undertaking, given the varying definitions, diverse data sources, and multitude of associated sociodemographic factors unique to this problem. Among those with hypertension, the prevalence of apparent resistant hypertension (ARHTN) was previously estimated at 10% to 30%, based on post hoc analyses of clinical trials.
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