Caulfield co-led and was a principal investigator (PI) on Anglo-Scandinavian
Cardiac Outcomes Trial (ASCOT). Hitman co-led and was a PI on Collaborative
AtoRvastatin Diabetes Study (CARDS). These studies dramatically
changed national and international guidance for diabetes, hypertension and
cholesterol, leading to widespread and far-reaching changes in management
of common and potentially fatal risk factors. For example, the proportion
of hypertensive patients in England with good BP control (<140/90) rose
from 52% in 2006 to 62% in 2011; the mean total cholesterol level of the
population has fallen by 0.5 Mmol/L between 1998 and 2011.
Before the Hypertension in the Very Elderly Trial (HYVET) it was not
clear whether people aged 80 and over with hypertension should receive
antihypertensive treatment. The over 80s are one of the fastest growing
groups in society and are at high risk of hypertension and its sequelae
due to age. HYVET demonstrated benefit of treatment including reduced
mortality and cardiovascular comorbidity. Guidelines around the world for
the treatment of hypertension have changed as a result. In the UK it is
proposed that the Quality Outcomes Framework (QOF) for GPs now includes
those over 80 and uses the target blood pressure used in HYVET.
More than half of UK adults aged over 45 years have high cholesterol
levels, the major modifiable risk factor for cardiovascular disease (CVD).
Over the past 20 years, University of Glasgow researchers have led
numerous landmark clinical trials establishing the benefits of statins for
CVD prevention. High-profile international clinical guidelines on lipid
lowering cite these studies in the key evidence base for recommendations
to guide statin use, demonstrating the considerable influence this work
exerts on current clinical practice and public health. This has driven the
global uptake of statins and provided the evidence-base for CVD risk
assessment and prevention strategies that are now implemented worldwide.
The use of statins has transformed patient care, provided a cost-effective
prevention strategy for healthcare providers and made major contributions
to the falling CVD mortality rates across Europe and the US.
The Collaborative Atorvastatin Diabetes Study (2004), led by researchers
at the University of Manchester (UoM), established the efficacy of statin
therapy in the prevention of atherosclerotic cardiovascular disease (CVD)
among patients with diabetes. The research challenged the previously held
view that, since CVD risk is markedly raised in people with diabetes even
when blood cholesterol levels are normal, statins were unlikely to be
beneficial for this group. These key findings have informed clinical
guidelines governing the use of statin therapy in the UK (NICE, SIGN) and
internationally (American Heart Association and the American Diabetes
Association, ESC, EAS), ensuring that statins are now considered for all
Pulmonary arterial hypertension (PAH) is a fatal disease that typically
affects women in their childbearing years. Professor Wilkins led a
research team at Imperial College that identified phosphodiesterase type 5
(PDE5) as a drug target in the lungs of patients with PAH. Imperial
validated the target in cell and animal models and demonstrated proof in
patients that Sildenafil, a PDE5 inhibitor, was an effective treatment for
PAH. Professor Wilkins conducted a clinical study to compare the effect of
oral Sildenafil with Bosentan, the only other available oral therapy for
PAH at the time. This study was the first, and remains the only,
head-to-head study of two treatments for PAH. Sildenafil demonstrated
comparable efficacy, had a greater effect on reducing cardiac mass (an
integrated measure of heart work) and was well tolerated.
Sildenafil is now the most commonly prescribed drug for PAH. It is the
most cost-effective, as judged by a technology appraisal initiated by
NICE. National and international guidelines recommend Sildenafil as a
first line treatment for patients in functional classes II and III
pulmonary hypertension. Worldwide sales of sildenafil (Revatio®) for the
management of PAH were $500m in 2010. With the expiration of the patent
the cost of treatment will fall further.
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.
Research led by Professor Brown has led to widespread changes in clinical
practice regarding the management of Hypertension. Following his
demonstration that patients' response to drugs for Hypertension is
variable (in a systematic manner), subsequent clinical guidelines
acknowledged the variability among patients, and changed from recommending
the same treatment for all patients, to an algorithm based on the
Cambridge AB/CD rule. The simplicity of the AB/CD rule led to popularity
among doctors, and adoption by national bodies — British Hypertension
Society, NICE, and foreign guidelines, and by textbooks of Medicine. The
guidelines arising from his research have contributed to improved health
outcomes in the UK. Specifically, NICE's simple and rational guidance how
to reach strict targets for blood pressure is credited with changing the
UK from the poorest to best performing country in Europe.
Impact: Health and welfare; a clinical trial demonstrated that
statin therapy is ineffective in aortic stenosis; this informed
international guidelines and changed clinical practice.
Significance: Unnecessary statin therapy is avoided in up to
500,000 people in the UK alone, saving the NHS £169M p.a. Known statin
side-effects of myalgia or hepatic dysfunction are avoided in 30,000
Beneficiaries: Patients with aortic stenosis; the NHS and
healthcare delivery organisations, the economy.
Attribution: Newby and Boon, UoE, undertook the first
investigator-led randomised controlled trial of statin therapy in aortic
stenosis: the SALTIRE trial.
Reach: Aortic stenosis affects 2% of people over 65. The SALTIRE
trial results informed European and N American guidelines and have
impacted the treatment of millions of people globally.
Novel work undertaken at this centre has demonstrated that vitamin B2
(riboflavin) can significantly decrease BP, specifically in people with a
common genetic variant affecting the folate-metabolising enzyme MTHFR. The
extent of BP-lowering demonstrated is as good as that expected from BP-lowering drugs and much better than that found with common dietary
approaches and furthermore, the effect is independent of concurrent
BP-lowering drugs. These findings offer a simple, cost-effective targeted
treatment for the management of BP in this genetically at-risk group. The
global prevalence of this genetic variant is 10% but can be as high as 32%
in other countries such as Mexico and Northern China.
Studies coordinated by the University of Oxford's Clinical Trial Service
Unit (CTSU) within the Nuffield Department of Population Health (NDPH)
have strongly influenced the labelling of statin medication
internationally, treatment guidelines, and the resulting changes in
prescribing have contributed to reductions in mortality and morbidity from
heart attack and ischaemic stroke in many countries. CTSU's randomised
trials and meta-analyses of trials have shown that lowering low-density
lipoprotein (LDL) cholesterol safely reduces the risk of heart attacks,
strokes and revascularisation procedures in a wide range of people, and
work conducted in collaboration with the NDPH's Health Economic Research
Centre has provided clear evidence of cost-effectiveness of statins.