1
Clinical characteristics, antihypertensive medication use and blood pressure control
among patients with treatment resistant hypertension: the SPIRIT study
Cheryl Carcel,
a,b,c
Bruce Neal,
a,b,d
Suzanne Oparil,
e
Kris Rodgers,
a
Krzysztof Narkiewicz,
f
Ji
Guang Wang,
g
Ernesto L. Schiffrin,
h
Neil Poulter,
i
Michel Azizi,
j
John Chalmers
a,c
a
The George Institute for Global Health, University of New South Wales, Sydney, New
South Wales, Australia
b
The University of Sydney, Sydney Medical School, Sydney, New South Wales, Australia
c
Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
d
Department of Epidemiology and Biostatistics, School of Public Health, Faculty of
Medicine, Imperial College London, United Kingdom
e
Vascular Biology and Hypertension Program, Division of Cardiovascular Disease,
Department of Medicine, School of Medicine, The University of Alabama at Birmingham,
Birmingham, Alabama, USA
f
Department of Hypertension and Diabetology, Medical University of Gdansk, Gdansk,
Poland
g
Shanghai Key Laboratory of Hypertension, Department of Hypertension, Centre for
Epidemiological Studies and Clinical Trials, The Shanghai Institute of Hypertension, Ruijin
Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
h
Lady Davis Institute and Department of Medicine, Jewish General Hospital, McGill
University, Montreal, Quebec, Canada
i
Imperial Clinical Trials Unit, Imperial College London, London, U.K.
j
University Paris Descartes, Paris, France; Assistance-Publique Hôpitaux de Paris, Hôpital
Européen Georges Pompidou, Hypertension Unit, Paris F-75015, France; Institut national de
la santé et de la recherche médicale, Centre d'Investigation Clinique 1418, Paris, France.
Word Count: 4949 Abstract: 249 Title: 18
Tables: 4 Figures: 2 Supplemental Table: 7
Short title: Treatment resistant hypertension
Corresponding author:
Professor John Chalmers
Address: The George Institute for Global Health
Level 10, King George V Building, 83-117 Missenden Road,
Camperdown NSW 2050 Australia
Email: chalmers@georgeinstitute.org.au
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Sources of funding
This research project was supported by Actelion Pharmaceuticals Ltd. and after Actelion’s
demerger to Idorsia in June 2017; and The George Institute for Global Health. The content is
solely the responsibility of the authors and does not necessarily represent the official views of
Idorsia. B. Neal is supported by an NHMRC Principal Research Fellowship.
Conflict of interest
B Neal reports a grant for the SPIRIT study from Idorsia, and grants for a clinical trial from
Janssen, honoraria and travel reimbursement from Janssen and advisory board fees from
Janssen outside of the submitted work, all of which were paid to his institution.
S Oparil reports research grants/personal fees/non-financial support from 98point6, Inc.,
Actelion/George Clinical, Bayer, Idorsia, NIH/NIAMS, Novartis, Pfizer, ROX Medical and
Vascular Dynamics and served as Director/PI of SPRINT UAB CCN and as sub-investigator
of a SPRINT UAB Clinical Site.
N Poulter has received financial support from several pharmaceutical companies which
manufacture BP-lowering agents, for consultancy fees (Servier), research projects and staff
(Servier, Pfizer) and for arranging and speaking at educational meetings (AstraZeneca, Lri
Therapharma, Napi, Servier and Pfizer). He holds no stocks and shares in any such
companies.
J Chalmers reports research grants and honoraria from Servier for the ADVANCE trial,
outside the submitted work and a grant for SPIRIT from Idorsia.
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ABSTRACT
Objective: We evaluated the characteristics of patients with treatment resistant hypertension
(TRH) and the prevalence of TRH in a large multi-country sample of specialist tertiary
centres.
Methods: The Survey of PatIents with treatment ResIstant hyperTension (SPIRIT) study was
a retrospective review of medical records of patients seen at tertiary centres located in
Western Europe, Eastern Europe, North America, South America, Australia and Asia. Data
on demographics, medical history and medication use were extracted from medical records.
Prevalence and incidence of TRH were based upon estimated catchment populations.
Results: 1555 patients from 76 centres were included, mostly from centres that specialise in
hypertension (55%), cardiology (11%) or nephrology (19%). Mean age was 64, 60% were
male, 62% were Caucasian, 36% had chronic kidney disease, 41% had diabetes, 12% were
smokers and 31% had a previous cardiovascular event. Daytime and night time ambulatory
blood pressure (BP) was the most frequently used measurement for diagnosis (82%). 95%
patients were prescribed diuretics, 93% an inhibitor of the renin-angiotensin system, 86% a
calcium channel blocker, 74% a beta-blocker and 36% an aldosterone antagonist. The overall
estimated mean incidence of TRH was 5.8 per 100,000 per year (ranging between 2.3 and
14.0 across regions) and the corresponding estimated mean prevalence of TRH was 23.9 per
100,000 (ranging between 7.6 and 90.5 across regions).
Conclusion: Observed variation likely reflects real differences in patient characteristics and
physician management practices across regions and specialities but may also reflect
differences in patient selection and errors in estimation of catchment population across
participating centres.
CONDENSED ABSTRACT
Data on clinical characteristics and management of patients with treatment resistant
hypertension (TRH) by specialty clinic is limited. We found differences which are likely the
consequence of the significant number of centres in the study that identified cardiology and
nephrology as their specialty. Despite being prescribed 3 and ≥ 4 antihypertensive classes,
TRH patients continue to have poorly controlled BP. There may be under utilization of
aldosterone antagonists in some patients. These data suggest the need for optimization of
treatment and the development of more effective therapeutic strategies.
Key words: hypertension, treatment-resistant, prevalence, incidence, region, specialty
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INTRODUCTION
Globally, over 1.4 billion people have hypertension with the proportion diagnosed and treated
varying considerably between continents and countries.[1, 2] Fewer than one third of those
prescribed treatment have their blood pressure (BP) controlled. This occurs despite extensive
knowledge about how to make the diagnosis of hypertension, the availability of numerous
antihypertensive drug classes and widespread consensus about management guidelines.[3-5]
Treatment resistant hypertension (TRH) is a diagnosis made for a subset of individuals with
uncontrolled BP levels.[6] TRH is present amongst individuals in which secondary causes of
hypertension have been excluded when either BP levels remain above thresholds while the
patient is using three or more different anti-hypertensive drug classes including a diuretic at
optimal or maximum tolerated doses, or when BP levels are controlled only by the use of four
or more different antihypertensive drug classes including a diuretic.[3, 5-8]
In a recent meta-analysis of 961,035 hypertensive individuals managed at specialist centres
around the world, the prevalence of TRH was estimated as 13.7% in observational studies
and 16.3% in clinical trials.[9] Amongst the studies contributing to the overview, the
repeated measures of BP required to obtain a robust estimate of true average BP for an
individual were not always available and it was recognised that over-estimation of the
prevalence of TRH was likely.[9] It is also of note that this prevalence estimate applies only
to a high risk subset of hypertensive patients who have been referred to a specialist centre.
Individuals with TRH are more likely to be male, obese, diabetic and to have previous
cardiovascular disease.[10, 11] There have also been reported differences in the strategies
used for diagnosis and treatment between centres, though most prior studies of patient
characteristics have been either single centre investigations done in primary care[12, 13] or
have been conducted in populations of limited diversity.[11, 14]
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Accordingly, there remains some uncertainty about the prevalence of TRH, the characteristics
of patients with TRH and the way that patients with TRH are managed around the world.
Almost certainly TRH affects only a small proportion of individuals with hypertension but
because hypertension is in itself very common it may nonetheless affect a substantial number
of individuals.
The objectives of this study were to quantify and compare the characteristics of patients with
TRH in a large multi-country sample of specialist clinical centres and to make estimates of
the incidence and prevalence of TRH in the general populations of different countries.
METHODS
The Survey of Patients with treatment Resistant hyperTension (SPIRIT) study was a
retrospective review of medical records relating to patient consultations at clinical centres
with particular expertise in the diagnosis and management of TRH. The SPIRIT study
protocol was approved by the Ethics Committees at participating institutions. All data
collected were de-identified. Patient consent was only required in some countries, as directed
by the responsible Ethics Committees. Requests for access to the de-identified data that
underlie the study results should be made to datasharing@georgeinstitute.org. We will
provide data to researchers with a methodologically sound proposal, and will work with
interested parties to define and operationalise a data access agreement.
Centre selection
The study was conducted in 76 clinical centres in 15 countries divided into regions described
as Western Europe (Belgium, France, Germany, The Netherlands, Switzerland and the United
Kingdom), Eastern Europe (the Czech Republic, Poland and Hungary), North America (the
United States and Canada), South America (Argentina), Asia (China and South Korea) and
Australia. Potential clinical centres were included or excluded based upon a feasibility
