Epidemiology of Resistant Hypertension in Canada - 2
Epidemiology of Resistant Hypertension in Canada - 2
Epidemiology of Resistant Hypertension in Canada - 2
Clinical Research
Epidemiology of Resistant Hypertension in Canada
Alexander A. Leung, MD, MPH,a,b Jeanne V.A. Williams, MSc,b Karen C. Tran, MD, MHSc,c and
Raj S. Padwal, MD, MScd
a
Department of Medicine, University of Calgary, Calgary, Alberta, Canada
b
Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada
c
Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
d
Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
ABSTRACT
RESUM
E
Background: Resistant hypertension is associated with cardiovascular Contexte : L’hypertension re sistante au traitement est associe e à
morbidity and mortality. The objective of this study was to estimate the une morbidite et une mortalite cardiovasculaires. L’objectif de
prevalence of apparent treatment-resistant hypertension in Canadian cette etude e tait d’estimer la pre valence de l’hypertension appa-
adults and examine the characteristics of those affected. remment re sistante au traitement chez les adultes canadiens et
Methods: A nationally representative cross-sectional study was con- d’examiner les caracte ristiques des personnes qui en e taient
ducted with the use of Canadian Health Measures Survey (2007-2017) affectees.
data. The frequency of respondents with uncontrolled blood pressure Methodes : Une e tude transversale repre sentative, à l’e
chelle natio-
despite 3 or more antihypertensive medications of different drug nale, a e te
mene e à l’aide des donne es de l’Enquête canadienne sur
classes (and at least 1 agent being a diuretic), or treatment with 4 or les mesures de la sante (2007-2017). On a de termine
la frequence
more agents regardless of blood pressure, was determined. des participants dont la pression arte rielle n’e
tait pas maîtrise
e malgre
Results: A total of 245,700 people were identified to have apparent la prise de trois me dicaments antihypertenseurs ou plus comprenant
treatment-resistant hypertension, representing 5.3% (95% confidence rentes classes de me
diffe dicaments (dont au moins un agent e tant un
interval [CI] 4.5%e6.2%) of adults treated for hypertension in Canada. tique), ou le traitement avec quatre agents ou plus, quelle que
diure
Respondents who had uncontrolled blood pressure with 3 or more soit la pression arterielle.
Blood pressure (BP) control is of enormous clinical and public Patients who are treated yet remain uncontrolled represent
health importance owing to the high prevalence of hyper- an important segment of the population. Apparent treatment-
tension, detrimental consequences of uncontrolled BP, and resistant hypertension (aTRH) may be the result of inaccurate
proven benefits of reducing high BP in terms of lowering the BP measurement, suboptimal medication regimens, medica-
risks of cardiovascular disease, kidney failure, and death.1,2 tion nonadherence, or unrecognised secondary causes of hy-
Even so, there has been a growing care gap over the past pertension, all of which may be potentially amenable to
decade in Canada, with BP control dropping from nearly 70% targeted interventions.5,6 Compared with other forms of hy-
to less than 60% in recent years,1 a finding associated with a pertension, the presence of aTRH is associated with an
corresponding rise in the rate of cardiovascular death since increased risk of cardiovascular morbidity and mortality,
2010.3 As such, a better understanding of the factors making identification of these individuals all the more
contributing to uncontrolled BP in Canada is urgently important.7-9
needed.4 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.
Received for publication November 10, 2021. Accepted January 27, 2022. Addressing this, we used the Canadian Health Measures
Corresponding author: Dr Alexander A. Leung, Departments of Medicine Survey (CHMS) to estimate the prevalence of aTRH among
and Community Health Sciences, University of Calgary, 1820 Richmond Canadian adults aged 20 to 79 years, and examined the
Road SW, Calgary, Alberta T2T 5C7, Canada. Tel.: þ1-403-955-8358; fax:
þ1-403-955-8249.
characteristics of those affected in order to determine who
E-mail: aacleung@ucalgary.ca may potentially benefit from specialised diagnostic workup,
See page 686 for disclosure information. specific treatments, or targeted interventions.
https://doi.org/10.1016/j.cjca.2022.01.029
0828-282X/Ó 2022 The Authors. Published by Elsevier Inc. on behalf of the Canadian Cardiovascular Society. This is an open access article under the CC BY-NC-
ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
682 Canadian Journal of Cardiology
Volume 38 2022
antihypertensive drugs were more likely women (55.8%, 95% CI Resultats : Au total, 245 700 personnes ont e te identifie
es comme
41.1%-70.4%), 70 years of age or older (45.3% 95% CI 32.8%-57.9%), souffrant d’une hypertension apparemment re sistante au traitement, ce
and overweight or obese (84.2%, 95% CI 72.3%-96.1%). Respondents qui represente 5,3 % (intervalle de confiance [IC] à 95 % : 4,5 %-6.2 %)
with apparent treatment-resistant hypertension also had a high likeli- s pour hypertension au Canada. Les participants dont
des adultes traite
hood of chronic kidney disease (36.0%, 95% CI 21.4%-50.6%), dia- la pression arte rielle n’e tait pas contrôle e par au moins trois
betes (35.2%, 95% CI 21.7%-48.7%), dyslipidemia (68.0%, 95% CI medicaments antihypertenseurs e taient le plus souvent des femmes
55.2%-80.8%), and history of heart attack (9.9%, 95% CI 4.8%-15.1%) (55,8 %, IC à 95 % : 41,1 %-70,4 %), e taient âge s de 70 ans ou plus
or stroke (7.1%, 95% CI 0-14.4%). (45,3 %, IC à 95 % : 32,8 %-57,9 %) et pre sentant une surcharge
Conclusions: Despite being prescribed at least 3 antihypertensive ponde rale ou une obe site
(84,2 %, IC à 95 % : 72,3 %-96,1 %). Les
drugs, a considerable proportion of Canadians, especially women, have sentant une hypertension apparemment re
participants pre sistante au
difficulty achieving blood pressure control, predisposing them to a traitement avaient e galement une forte probabilite de souffrir d’une
higher risk of cardiovascular complications and death. maladie re nale chronique (36,0 %, IC à 95 % : 21,4 %-50,6 %), de
diabète (35,2 %, IC à 95 % : 21,7 %-48,7 %), de dyslipide mie (68,0 %, IC
à 95 % : 55,2 %-80,8 %) et d’ante ce
dents de crise cardiaque (9,9 %, IC à
95 % : 4,8 %-15,1 %) ou d’accident vasculaire ce re
bral (7,1 %, IC à
95 % : 0-14,4 %).
Conclusions : Bien qu’au moins trois me dicaments antihypertenseurs
te
leur ait e prescrits, une proportion conside rable de Canadiens, sur-
tout des femmes, ont de la difficulte à contrôler leur pression arterielle,
ce qui les predispose à un risque plus e leve de complications car-
diovasculaires et de de cès.
Statistical analysis half of these people with aTRH had uncontrolled BP even
though they reported taking at least 3 antihypertensive med-
Data from all available cycles of the CHMS were pooled
ications, while the remainder were taking at least 4 antihy-
by applying respondent-specific survey weights to generate
pertensive medications in the past month. In our sensitivity
population-representative estimates, and variances were
analyses, the prevalence of aTRH and its individual compo-
determined with the use of bootstrapping to account for the
nents were broadly similar after adjusting for possible differ-
complex survey design.13-15,26 The proportion of re-
ences in measurements obtained using automatic oscillometric
spondents with aTRH was calculated and descriptive statis-
devices vs traditional manual BP measurements, as well as
tics of their characteristics reported. In adherence with
when a threshold of 130/80 mm Hg for high BP was applied
Statistics Canada’s policy, absolute numbers were rounded to
(Supplemental Table S2).
the nearest 100, and estimates based on sample sizes of fewer
Adults with aTRH had mean SBP and DBP of 132.6 and
than 5 respondents were suppressed. These cases were
71.8 mm Hg, respectively (Table 1). Those who had un-
handled either by omitting the corresponding cells or by
controlled BP despite taking 3 or more antihypertensive
combining multiple subgroups together to satisfy the re-
drugs had mean SBP and DBP of 150.8 and 79.1 mm Hg,
quirements for data release and publication. We conducted 2
and those who were taking 4 or more antihypertensive drugs
sensitivity analyses to facilitate comparisons1,18,19: first, rec-
(regardless of BP) had mean SBP and DBP of 118.0 and 65.8
ognising that BpTRU SBP and DBP measurements may be
mm Hg, respectively. Nearly all respondents were taking
slightly lower than conventional manual BP readings,27 we
diuretics and renin-angiotensin system inhibitors in the past
applied a validated correction27 and used the adjusted values
month, and more than a third were also taking beta-blockers
to determine the prevalence of hypertension and aTRH
and calcium channel blockers. Respondents with aTRH were
(defined by a mean SBP of 140 mm Hg or DBP of 90
typically older and more commonly men compared with
mm Hg); second, we examined the proportion of people
those with treated hypertension in general. Being overweight
with hypertension and aTRH according to the BP threshold
or obese and engaging in less than 150 minutes of moderate
provided by the American College of Cardiology and
to vigorous physical activity per week were nearly 10% more
American Heart Association guidelines (a mean SBP of
frequent in those with aTRH. Respondents with aTRH,
130 mm Hg or DBP of 80 mm Hg based on unadjusted
compared with those with treated hypertension in general,
BpTRU measurements).28
were twice as likely to have diabetes, chronic kidney disease,
We then assessed for predictors for aTRH among those
heart attack, stroke, or a family history of high blood pressure
who were treated for hypertension. Potential risk factors were
or premature cardiovascular disease. In contrast to most
selected a priori based on clinical reasoning and previous re-
patients with hypertension (where the risk of incident car-
ports.29 Logistic regression modelling was used to estimate
diovascular disease was estimated to be low to moderate),
risk ratios (RRs), adjusting for other covariates, and stratified
two-thirds of those with aTRH were at high cardiovascular
according to sex. The candidate variables were all dichoto-
risk based on the Framingham risk score.
mous, except age, which was modelled as a multicategoric
There were notable differences between respondents with
variable (with age bands corresponding to 20-59, 60-69, and
uncontrolled BP despite taking 3 or more antihypertensive
70-79 years) to allow for the possibility of nonlinear associa-
drugs vs those taking 4 or more drugs regardless of BP
tions. All statistical analyses were performed using Stata 16.0
achieved. The former were more commonly women (55.8%
(StataCorp, College Station, TX).
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
Results considerably lower prevalence of diabetes (35.2% vs 55.9%),
There was a total of 26,041,200 Canadian adults repre- dyslipidemia (68.0% vs 88.6%), and heart attack (9.9% vs
sented in the survey (rounded to the nearest 100) and 33.1%). While there were high levels of use of every major
5,820,400 of them had hypertension (23.2%, 95% CI antihypertensive drug class (including renin-angiotensin
22.1%-24.4%). Of these, 79.1% (95% CI 76.4%-81.8%) system inhibitors, diuretics, calcium channel blockers, and
were treated with at least 1 antihypertensive drug. Treated beta-blockers), the use of antihypertensive drugs from other
patients had a mean SBP and DBP of 122.9 and 73.7 mm categories was considerably less common among respondents
Hg, respectively, and they were taking an average of 1.8 who had uncontrolled BP on 3 or more drugs vs those who
antihypertensive medications in the past month (Table 1). were taking 4 or more drugs (10.5% vs 59.9%).
The mean age of treated individuals was 61.7 years, approx- After covariate adjustment, 4 risk factors were significantly
imately half were men, and the majority were white. Being associated with aTRH in adult men (Supplemental Table S3):
overweight or obese, engaging in less than 150 minutes of age from 70 to 79 years (compared with men aged 20 to 59
moderate to vigorous physical activity per week, and years: RR 5.0, 95% CI 1.6-16.2), being overweight or obese
consuming fruits and vegetables less than 5 times per day were (RR 2.5, 95% CI 1.1-5.9), chronic kidney disease (RR 1.9,
common: present in more than 80% of those treated. More 95% CI 1.1-3.2), and diabetes (RR 2.5, 95% CI 1.5-4.4).
than half had dyslipidemia, nearly one-third had diabetes, and Among adult women, age from 70 to 79 years was the only
more than 1 in 10 had chronic kidney disease. statistically significant predictor of aTRH (RR 2.7, 95% CI
Overall, aTRH was present in 245,700 of the sample, 1.1-6.7). Similarly to men, however, women with chronic
representing 5.3% (95% CI 4.5%-6.2%) of adults who were kidney disease and diabetes appeared to be at a 2-fold higher
treated for hypertension in Canada, and the prevalence was risk of aTRH, but these latter associations were not statisti-
similar in each cycle of the survey (Table 2). Slightly less than cally significant.
Leung et al. 685
Resistant Hypertension in Canada
medication combinations that are less likely to be effective). 2. Ettehad D, Emdin CA, Kiran A, et al. Blood pressure lowering for pre-
As such, we could not report on rates of resistant hyperten- vention of cardiovascular disease and death: a systematic review and meta-
sion, but only aTRH. Third, we could not confirm the analysis. Lancet 2016;387:957-67.
primary indication for taking an antihypertensive drug 3. Institute for Health Metrics and Evaluation: Global Burden of Disease
(ie, whether it was prescribed for high BP or for another Study. University of Washington. Available at: http://vizhub.healthdata.
condition, such as heart failure). Therefore, our estimated org/gbd-compare. Accessed January 19, 2021.
treatment rates may have been subject to some degree of
4. Feldman RD, Padwal RS, Tobe SW. The rise and fall of hypertension
misclassification, though this likely would have been small.43 control in Canada: the beginning of the end or the end of the beginning?
Fourth, we could not completely rule out misclassification Can J Cardiol 2021;37:679-82.
from a single visit office-based BP measurement. Still, unat-
tended automated office BP measurements are thought to 5. Burnier M, Wuerzner G, Struijker-Boudier H, Urquhart J. Measuring,
largely mitigate the white-coat effect,27,44 and compared with analyzing, and managing drug adherence in resistant hypertension. Hy-
pertension 2013;62:218-25.
the criterion standard of 24-hour ambulatory blood pressure
measurements, they have high specificity (81%-91%) for 6. Ruzicka M, Leenen FHH, Ramsay T, et al. Use of directly observed
detecting elevated BP.45 Fifth, we did not factor more therapy to assess treatment adherence in patients with apparent
intensive treatment goals for certain groups (eg, BP < 130/80 treatment-resistant hypertension. JAMA Intern Med 2019;179:1433-4.
mm Hg in people with diabetes, or SBP < 120 mm Hg in 7. Muntner P, Davis BR, Cushman WC, et al. Treatment-resistant hyper-
high-risk adults),46 but rather assumed a common BP target tension and the incidence of cardiovascular disease and end-stage renal
for all respondents because treatment decisions are frequently disease: results from the Antihypertensive and Lipid-Lowering Treatment
nuanced. Applying a lower BP target would doubtlessly have to Prevent Heart Attack Trial (ALLHAT). Hypertension 2014;64:
raised the prevalence of aTRH, which may have been one of 1012-21.
the reasons why our estimates were slightly lower than 8. Irvin MR, Booth JN 3rd, Shimbo D, et al. Apparent treatment-resistant
others.30,31 Finally, we identified a number of risk factors hypertension and risk for stroke, coronary heart disease, and all-cause
associated with aTRH, but causal relationships could not be mortality. J Am Soc Hypertens 2014;8:405-13.
established because data were cross-sectional. Further study is
needed to determine if treatment of modifiable risk factors 9. Daugherty SL, Powers JD, Magid DJ, et al. Incidence and prognosis of
resistant hypertension in hypertensive patients. Circulation 2012;125:
leads to improved long-term BP control.38
1635-42.
15. Statistics Canada: Canadian Health Measures Survey (CHMS) data user
Funding Sources
guide: cycle 3 November 2014. Available on request at: http://www.
This study was funded by the Canadian Institutes of statcan.gc.ca.
Health Research (project grant no 159533). Dr Leung is
supported by a Heart and Stroke Foundation National New 16. Statistics Canada: Canadian Health Measures Survey (CHMS) data user
Investigator Award. guide: cycle 4 December 2016. Available on request at: http://www.
statcan.gc.ca.
17. Statistics Canada: Canadian Health Measures Survey (CHMS) data user
Disclosures guide: cycle 5 October 2018. Available on request at: http://www.statcan.
Dr Padwal is CEO of mmHg Inc, a digital health company gc.ca.
that creates cloud-based solutions for remote patient moni- 18. Leung AA, Bushnik T, Hennessy D, McAlister FA, Manuel DG. Risk
toring and management. The other authors have no conflicts factors for hypertension in Canada. Health Rep 2019;30:3-13.
of interest to disclose.
19. Padwal RS, Bienek A, McAlister FA, Campbell NR. Epidemiology of
hypertension in Canada: an update. Can J Cardiol 2016;32:687-94.
References
20. NCD. Risk Factor Collaboration: Long-term and recent trends in hy-
1. Leung AA, Williams JVA, McAlister FA, et al. Worsening hypertension pertension awareness, treatment, and control in 12 high-income coun-
awareness, treatment, and control rates in Canadian women between tries: an analysis of 123 nationally representative surveys. Lancet
2007 and 2017. Can J Cardiol 2020;36:732-9. 2019;394:639-51.
Leung et al. 687
Resistant Hypertension in Canada
21. Carey RM, Calhoun DA, Bakris GL, et al. Resistant hypertension: 36. Durand H, Hayes P, Morrissey EC, et al. Medication adherence among
detection, evaluation, and management: a scientific statement from the patients with apparent treatment-resistant hypertension: systematic re-
American Heart Association. Hypertension 2018;72:e53-90. view and meta-analysis. J Hypertens 2017;35:2346-57.
22. Bryan S, Saint-Pierre Larose M, Campbell N, Clarke J, Tremblay MS. 37. Fontil V, Gupta R, Moise N, et al. Adapting and evaluating a health
Resting blood pressure and heart rate measurement in the Canadian system intervention from Kaiser Permanente to improve hypertension
Health Measures Survey, cycle 1. Health Rep 2010;21:71-8. management and control in a large network of safety-net clinics. Circ
23. Nerenberg KA, Zarnke KB, Leung AA, et al. Hypertension Canada’s Cardiovasc Qual Outcomes 2018;11:e004386.
2018 guidelines for diagnosis, risk assessment, prevention, and treatment
38. Blumenthal JA, Hinderliter AL, Smith PJ, et al. Effects of lifestyle
of hypertension in adults and children. Can J Cardiol 2018;34:506-25.
modification on patients with resistant hypertension: results of the
24. Bushnik T, Hennessy DA, McAlister FA, Manuel DG. Factors associated TRIUMPH randomized clinical trial. Circulation 2021;144:1212-26.
with hypertension control among older Canadians. Health Rep 2018;29:
3-10. 39. Gaddam KK, Nishizaka MK, Pratt-Ubunama MN, et al. Characteriza-
tion of resistant hypertension: association between resistant hypertension,
25. Coresh J, Selvin E, Stevens LA, et al. Prevalence of chronic kidney disease aldosterone, and persistent intravascular volume expansion. Arch Intern
in the United States. JAMA 2007;298:2038-47. Med 2008;168:1159-64.
26. Statistics Canada: Instructions for combining multiple cycles of Canadian 40. Brown JM, Siddiqui M, Calhoun DA, et al. The unrecognized prevalence
Health Measures Survey (CHMS) data 2017. Available at: http://www. of primary aldosteronism: a cross-sectional study. Ann Intern Med
statcan.gc.ca. 2020;173:10-20.
27. Myers MG, McInnis NH, Fodor GJ, Leenen FH. Comparison between
41. Williams B, MacDonald TM, Morant S, et al. Spironolactone versus
an automated and manual sphygmomanometer in a population survey.
placebo, bisoprolol, and doxazosin to determine the optimal treatment
Am J Hypertens 2008;21:280-3.
for drug-resistant hypertension (PATHWAY-2): a randomised, double-
28. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ blind, crossover trial. Lancet 2015;386:2059-68.
ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the
prevention, detection, evaluation, and management of high blood pres- 42. Cohen JB, Cohen DL, Herman DS, et al. Testing for primary aldoste-
sure in adults: a report of the American College of Cardiology/American ronism and mineralocorticoid receptor antagonist use among U.S. vet-
Heart Association Task Force on Clinical Practice Guidelines. J Am Coll erans: a retrospective cohort study. Ann Intern Med 2021;174:289-97.
Cardiol 2018;71:e127-248.
43. Wilkins K, Gee M, Campbell N. The difference in hypertension control
29. Egan BM, Zhao Y, Axon RN, Brzezinski WA, Ferdinand KC. Uncon- between older men and women. Health Rep 2012;23:33-40.
trolled and apparent treatment resistant hypertension in the United States
1988 to 2008. Circulation 2011;124:1046-58. 44. Roerecke M, Kaczorowski J, Myers MG. Comparing automated office
blood pressure readings with other methods of blood pressure measure-
30. Gee ME, Bienek A, McAlister FA, et al. Factors associated with lack of ment for identifying patients with possible hypertension: a systematic
awareness and uncontrolled high blood pressure among Canadian adults review and meta-analysis. JAMA Intern Med 2019;179:351-62.
with hypertension. Can J Cardiol 2012;28:375-82.
45. Viera AJ, Yano Y, Lin FC, et al. Does this adult patient have hyper-
31. Noubiap JJ, Nansseu JR, Nyaga UF, et al. Global prevalence of resistant tension? The rational clinical examination systematic review. JAMA
hypertension: a meta-analysis of data from 3.2 million patients. Heart 2021;326:339-47.
2019;105:98-105.
46. Rabi DM, McBrien KA, Sapir-Pichhadze R, et al. Hypertension Canada’s
32. Kovell LC, Harrington CM, Michos ED. Update on blood pressure
2020 Comprehensive guidelines for the prevention, diagnosis, risk
control among US adults with hypertension. JAMA 2021;325:586-7.
assessment, and treatment of hypertension in adults and children. Can J
33. Muntner P, Hardy ST. Update on blood pressure control among US Cardiol 2020;36:596-624.
adults with hypertensiondreply. JAMA 2021;325:587-8.
34. Sinnott SJ, Smeeth L, Williamson E, Douglas IJ. Trends for prevalence
and incidence of resistant hypertension: population based cohort study in Supplementary Material
the UK 1995-2015. BMJ 2017;358:j3984. To access the supplementary material accompanying this
35. Garg JP, Elliott WJ, Folker A, et al. Resistant hypertension revisited: a article, visit the online version of the Canadian Journal of
comparison of two university-based cohorts. Am J Hypertens 2005;18: Cardiology at www.onlinecjc.ca and at https://doi.org/10.101
619-26. 6/j.cjca.2022.01.029.