Redefining hypertension treatment practice to reduce primary and secondary stroke risk
Submitting InstitutionUniversity of Glasgow
Unit of AssessmentClinical Medicine
Summary Impact TypeHealth
Research Subject Area(s)
Medical and Health Sciences: Cardiorespiratory Medicine and Haematology, Clinical Sciences, Public Health and Health Services
Summary of the impact
Stroke is the leading cause of disability and a major cause of death in
the developed world. Hypertension (high blood pressure) is the single most
important modifiable risk factor for stroke, contributing to around 50% of
all events. University of Glasgow researchers have played lead roles in
the design, conduct and analysis of pivotal clinical trials on treatment
regimens for hypertension. These research findings have informed European
and UK hypertension and stroke guidelines, advancing treatment strategies,
and contributed to the observed ~25% reduction in the incidence of primary
(first) and secondary (recurrent) stroke.
Working at the forefront of hypertension and stroke research for more
than 40 years, investigators at the University of Glasgow are recognised
leaders in both laboratory-based and clinical research into the causes of
hypertension and its treatment. A theme of particular interest is the link
between hypertension and stroke. University of Glasgow researchers have a
global reputation in the design and execution of landmark clinical trials
in this area.
Perindopril Protection Against Recurrent Stroke Study (PROGRESS;
A University of Glasgow team — comprising Professors Kennedy Lees, John
Reid and Matthew Walters — led ground-breaking clinical studies of the
angiotensin-converting enzyme (ACE) inhibitor, perindopril, the first
long-acting, once-daily preparation available for use in hypertensive
patients. Previously, treatments that lowered blood pressure (BP) had been
shown to reduce the risk of primary stroke, but it was unclear whether
they also prevented secondary strokes. The University of Glasgow
researchers designed and led the pioneering PROGRESS randomised controlled
clinical trial, which established the safety and tolerability of
perindopril among healthy volunteers and patients with hypertension or
stroke (172 participating centres; 6,105 patients recruited). Members of
the University of Glasgow research team also played significant roles in
comparative studies of perindopril versus other BP-lowering drugs.
Eligibility criteria for patient enrolment was broad (including previous
stroke of any kind during the previous 5 years with no stroke-related
disability), thus providing a heterogeneous population in which to test
the efficacy of perindopril. The findings of PROGRESS (published in 2001)
were profound, showing that a perindopril-based regimen reduced the
overall relative risk of recurrent stroke by 28%. Results were
far-reaching for the management of stroke risk, suggesting that all
patients with stroke should receive BP-lowering therapy irrespective of
their actual BP reading; this strategy represented a major departure from
University of Glasgow researchers also led a very large epidemiological
study of recurrent stroke (5.1 million people in Scotland), evaluating
hospitalisations and outcomes over a 15-year period (1986-2001).3
By comparing data from 1986 with those from 2001, this study demonstrated
improved survival following stroke, with a 28% decreased risk of death and
a 27% decreased chance of hospitalisation for recurrent stroke. These
findings confirmed the value of secondary prevention strategies to improve
Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT; 1998-2002)4,5
ASCOT was the largest study of hypertension ever conducted in Europe.
University of Glasgow researcher Professor Gordon McInnes played an
integral role in the design, direction and management of the ASCOT trial,
and contributed greatly to patient recruitment. The ASCOT BP-lowering arm
(ASCOT-BPLA), which was led by McInnes and recruited 19,257 patients with
hypertension, was the first study to perform a head-to-head comparison of
two different BP-lowering treatment regimens on cardiovascular (CVD)
outcomes, including stroke. One treatment regimen combined perindopril
with amlodipine (a calcium-channel blocker), while the other combined
atenolol (a β-blocker) and thiazide (a diuretic). The
perindopril-amlodipine combination provided superior risk reduction over
the atenolol-thiazide combination for multiple CVD parameters, including a
23% reduction in the composite end point of fatal and non-fatal stroke.
The ambulatory BP-monitoring (ABPM) sub-study of ASCOT-BPLA tested whether
this difference in CVD outcomes between the two treatment regimens could
be attributed to the method used to monitor, and if so, whether ABPM a
more useful predictor of CVD risk than a single-visit clinic measurement.
Ambulatory BP-monitoring involves regular BP measurements during normal
living and working conditions over a 24-hour period. ASCOT-ABPM revealed
that people with high night-time ABPM readings were at increased risk of a
CVD event, demonstrating incremental utility over clinic BP measures in
this group of patients.
The two ASCOT studies clearly demonstrated the benefit of reducing CVD
risk and mortality through: i) choice of BP-lowering regimen and ii)
qualifying ABPM over single-visit BP readings in influencing CVD risk,
especially stroke. These findings challenged long-held prescribing
recommendations that first-line therapy for hypertension should comprise a
diuretic plus β-blocker.
Losartan Intervention For Endpoint reduction in hypertension study
LIFE was another breakthrough hypertension trial that investigated the
use of angiotensin II-receptor blockers (ARBs) among individuals with high
CVD risk. ARBs first became available in the mid-1990s; they display
similar benefits to ACE inhibitors but can potentially be offered as an
alternative treatment for patients unable to tolerate ACE inhibitors.
McInnes and Reid both played important roles in LIFE, with McInnes as the
Principal Investigator of the fastest recruiting site (Glasgow) in this
global multi-centre study. LIFE recruited 9,193 hypertensive patients and
compared the first ARB (losartan) with the established β-blocker,
atenolol. Treatment with losartan reduced both mortality and secondary CVD
events, including fatal and non-fatal stroke (25% reduction). LIFE was the
first study to directly compare the effects of ARBs and β-blockers on the
rates of stroke-related outcome, independent of BP reading.
Key Researchers: Kennedy Lees (Professor of Cerebrovascular
Medicine, 1985-present); John Reid (Regius Professor of Medicine and
Therapeutics, 1978-2010); Matthew Walters (Senior Lecturer in Medicine,
2003-2008; Reader, 2008-2010; Professor of Clinical Pharmacology,
2010-present); Gordon McInnes (Professor of Clinical Pharmacology,
1980-2007). Key positions held in clinical trials: PROGRESS: Lees
and Reid, members of Management Committee; regional Principal
Investigators. ASCOT: McInnes, Steering Committee; Lead for ASCOT-ABPM
sub-study; Regional Trial Coordinator for UK and Ireland. LIFE: McInnes
and Reid, Principal Investigators, Glasgow study centre. Key research
collaborators: PROGRESS: Stephen MacMahon and John Chalmers
(University of Sydney, Australia). ASCOT: Neil Poulter and Peter Sever
(Imperial College, London); Björn Dahlöf (Sahlgrenska University Hospital,
Sweden). LIFE: Dahlöf (as above).
References to the research
Details of the impact
In the UK, approximately 152,000 strokes cause around 50,000 deaths
annually; furthermore, 1.1 million stroke-related deaths are recorded in
Europe each year. The resulting economic burden attributed to stroke in
the UK alone is £3.75 billion. University of Glasgow research has driven
improvements in management of patients with hypertension, exerting marked
influence on stroke prevalence and fatality by underpinning clinical
guideline recommendations and implementation.
Clinical guidelines for hypertension and stroke
The University of Glasgow's international reputation in hypertension and
stroke research has invited involvement in clinical guideline development
at the highest level. Professor Anna Dominiczak — Regius Professor of
Medicine in the University's Institute of Cardiovascular and Medical
Sciences — held a key role on the Scientific Council for the 2013 European
Society for Hypertension (ESH) guidelines. Lees currently serves as
President Elect of the European Stroke Organisation (ESO) and was a
co-author of the 2008 ESO guidelines. The University of Glasgow's
contribution to landmark studies on hypertension provided a strong
evidence-base that has informed both European and UK guideline
recommendations published since 2008.
2013 ESH/European Society of Cardiology (ESH/ESC) joint guidelines for
the management of arterial hypertensiona
- The PROGRESS,1 ASCOT-BPLA,4 and LIFE6
studies are included in the key underpinning evidence (Table 16) used to
develop the `Summary of recommendations on treatment strategies and
choice of drug' (Section 5.2.3), which list a series of
hypertension treatment paradigms relating to ACE inhibitors,
calcium-channel blockers and ARBs.
- The influence of PROGRESS1 in defining the clinical utility
of BP reduction in preventing recurrent stroke is highlighted by its
citation as one of only two to three references underpinning the
following recommendations: "Antihypertensive treatment is recommended
in hypertensive patients with a history of stroke or TIA even when
initial SBP is in the 140-159 mmHg range" and "In hypertensive
patients with a history of stroke or TIA, a SBP goal of <140 mmHg
should be considered" (Section 16.10.4).
2008 ESO guidelines for management of ischaemic stroke and transient
- The BP-lowering effects of losartan demonstrated in the LIFE6
study are cited in the key underpinning evidence base for the following
recommendation to reduce vascular risk factors and prevent first-time
stroke (primary prevention): "Blood pressure should be checked
regularly. It is recommended that high blood pressure should be
managed with lifestyle modification and individualized pharmacological
therapy (Class I recommendation, Level A evidence) aiming at normal
levels of 120/80 mmHg."
- The value of the PROGRESS1 findings in demonstrating BP
reduction to prevent recurrent stroke (secondary prevention) is cited in
the evidence base to support the following: "It is recommended that
BP be checked regularly. BP lowering is recommended after the acute
phase, including in patients with normal BP (Class I recommendation,
Level A evidence)."
Effective management of hypertension has the greatest impact on reducing
stroke incidence. Consequently, national guidance documents that align
with international guideline recommendations play an important role in
influencing patient care at a local level. Guidelines developed by the UK
National Institute for Health and Care Excellence (NICE) and the Scottish
Intercollegiate Guidance Network (SIGN) are instrumental in driving best
practice within the NHS.
2011 NICE guideline Hypertension — the clinical management of primary
hypertension in adultsc This guideline replaces NICE CG34
(2006), in which the findings ASCOT-BPLA4 and LIFE6
were extensively cited in the evidence synthesis for recommendations on
hypertension treatment strategies and algorithms (i.e. preferential use of
ACE inhibitors or ARBs over β-blockers). The 2011 update (CG127) cites
PROSPER,1 ASCOT-BPLA4 and LIFE in the evidence base;6
furthermore, many of the original recommendations supported by University
of Glasgow research remain in CG127, testament to the enduring impact of
this body of work.
2008 Scottish Intercollegiate Guidelines Network (SIGN) guideline 108
— management of patients with stroke or TIAd
SIGN has responsibility for development of evidence-based clinical
guidelines for use within NHS Scotland. The SIGN 108 recommendations on
the secondary prevention of stroke draw directly on the University of
- "All patients with a previous stroke or TIA should be considered
for treatment with an ACE inhibitor (for example, perindopril) and
thiazide (for example, indapamide) regardless of blood pressure,
unless contraindicated." PROGRESS1 is cited in the
underpinning evidence for this Class A advisory on the secondary
prevention of ischaemic stroke.
"Lowering blood pressure (non-acutely) following ICH using a
combination therapy of ACE inhibitor and thiazide diuretic
should be considered to prevent further vascular events."
PROGRESS1 is cited in the underpinning evidence for this
Class A advisory on the secondary prevention of haemorrhagic stroke.
Uptake of UK clinical guidance
A 2010 NICE implementation uptake report evaluated national trends
following publication of NICE CG34 (2006).e Findings confirmed
a sharp drop in the prescribing of β-blockers from 14% (July-September
2005) to 3% (April-June 2009), while use of ACE inhibitors rose from 27%
to 48% in the same period. By June 2009, 75% of all newly diagnosed
hypertensive patients aged less than 55 years were prescribed either an
ACE inhibitor or an ARB.
In Scotland, SIGN takes a proactive approach to dissemination and
implementation of its guidelines. Named individuals within each of the 14
regional Scottish Health Boards are recruited to promote new and updated
SIGN guidelines and to draw up plans for their subsequent implementation.
In the 2 months following publication, SIGN 108 was downloaded 66,150
times.f In addition, the following national strategies and
action plans draw on the recommendations of SIGN 108: i) Better Heart
Disease and Stroke Care Action Plan (2009) and ii) Clinical
Standards for Stroke Services (2009).f
The Quality and Outcomes Framework (QOF) is an incentive scheme for GP
practices providing financial rewards for patient care across multiple
disease domains. Where available, QOFs are based on NICE and SIGN
guidelines. The SIGN 108 and NICE CG34 guidelines are cited in the
2011-2012 QOF guidance on stroke and hypertension, respectively. PROGRESS1
is cited in the evidence base for QOF stroke indicator 6 (secondary
prevention); around 85% of patients in England with a previous stroke
received treatment to target BP-lowering during 2011-2012.g
Sources to corroborate the impact
guidelines for the management of arterial hypertension, 2013
[doi:10.1097/01.hjh.0000431740.32696.cc]. Cites PROGRESS (ref 296; p1304,
1306, 1313, 1314, 1323, 1324); ASCOT-BPLA (ref 423; p1310, 1313, 1314);
LIFE (ref 457; p1313, 1314). See Table 16 (p1314); Section 5.2.3
(p1315-1316); Section 6.10.4 (p1324).
guidelines for management of ischaemic stroke and transient ischaemic
attack, 2008. Cites PROGRESS (ref 290; p39, 83); LIFE (ref 213;
p30). See recommendations (p29, 38)
CG127 guideline on the clinical management of primary hypertension in
adults, 2011. Cites PROGRESS (ref 500; Table 3, p201); ASCOT-BPLA
(ref 157; p206, 248); LIFE (ref 154; p35).
d. SIGN 108 guidelines
on management of patients with stroke or TIA, 2008. Cites PROGRESS
(ref 228, p37 and 40).
CG34 implementation uptake report, 2010. (Figure 4, Table 2).
f. SIGN 108 download data — available on request.
guidance for GMS contract (p52, 53, 56) and QOF
data (STROKE06), 2011-2012.