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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 diabetic patients.
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 patients.
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.