Current Programme of Research
I am establishing a large cohort study for observational research in south west London (The TOGETHER Study) in approximately 250,000 individuals by using, routine electronic health records of those attending the NHS vascular health checks and via linkage to disease/outcome registries. We have been awarded seed funding for 3 years to begin this work which is Public Health England Endorsed and CAG approved. This will allow us to not only study the cross sectional burden of cardiovascular (CV) risk factors across diverse ethnic groups and socioeconomic strata, but also assess the relationship of a diverse group of risk factors by age, gender, and ethnicity to CV outcomes. In time I plan to build upon this baseline data and embed novel clinical risk markers into routine clinical practice in the NHS vascular health checks in a cost effective manner during resurveys to establish a large scale bioresource, e.g. for drug discovery and for improving risk prediction on a larger scale than hitherto possible. This will inform patient care among those often missed in bespoke studies. This resource could in time be used to conduct clinical trials with deeply phenotyped individuals, reducing screen failures and recruitment time, and therefore can be conducted efficiently at a fraction of the cost of bespoke studies.
I am also co-leading with the University of Manchester the largest UK population-based study of women (the UK Womens Heart Study, with an age range 30-60y) with over 25 years of follow up already in 22,000 women. Blood and DNA have been stored at baseline and after linkage to a range of vascular and non-vascular outcomes, and my collaborators and I will test a number of blood based hypotheses. My specific areas of interest in this cohort are the role of novel markers of lipids, lipoproteins, inflammation and thrombosis and their impact on CVD. This cohort also opens up the possibility of studying cancers and other diseases effecting women.
Familial Hypercholesterolaemia (FH) is the most common autosomal dominant disorder affecting man (1:200-250) and is underdiagnosed and undertreated with catastrophic consequences for those affected. To provide data on how FH is diagnosed and treated and to ascertain the consequences of current clinical practice, I have established a global registry of FH (FH Studies collaboration) which has attracted four grants. This registry is led by my group and endorsed by the European Atherosclerosis Society and extends across Europe, Africa, South America and the Asia Pacific region.
I have been working with Clinical Practice Research Datalink (CPRD) and the Imperial Clinical Trials Unit to bring more clinical trials to the UK and led by the UK. This is an extension of my current role as National Lead Investigator and Steering Committee Member on many global trials. I am also working with CPRD to try and develop clinical trial methodology and trial capacity which will streamline screening, recruitment and management reducing costs of running trials in the UK.
Impact of Research to Date
The work conducted so far on statins has informed several international guidelines for heart disease, which are cited as proving evidence for specific approaches to patient care. For instance the demonstration of the early benefits of intensive statin therapy over standard therapy within 30 days of an ACS event is the best guidance anywhere for this approach in clinical practice (ESC guidelines). The demonstration that older patients derive greater absolute benefit from intensive lipid lowering and that this can be done safely after an ACS should ensure that these often neglected individuals who do not receive evidence based care are appropriately treated (ACC/AHA guidelines for treatment of the elderly patient with MI).
Our recent work on more vs less intensive glycaemic control shows that more intensive therapy reduces coronary heart disease (CHD) events without an excess risk of death, thus reassuring clinicians and guidelines committees. We have also demonstrated that triglycerides are unlikely to be causal for CHD risk and screening can be simplified by using non-HDL-C and HDL-C informing EAS/ESC guidelines. Studies of dysglycaemia have demonstrated that the risk of cardiovascular disease (CVD) from dysglycaemia is modest with a non-linear relationship between risk and CVD.
Most recently our work on statins has shown a dose dependent increase in the risk of diabetes which have led to FDA and EMEA label changes for statins. Our work on aspirin in primary prevention has shown that aspirin does not reduce cardiovascular death and the benefits on non-fatal MI are offset by a significant increase in bleeding. This has lead many guidelines to discontinue routine aspirin use in primary prevention.
Much of my work has attracted high profile attention in the lay press. I therefore have frequently engaged with media over the last 6 years to disseminate key research messages in a simple format for the general public. Furthermore, I frequently represent the British Cardiovascular Society in many of these engagements to contextualise new and often controversial research findings on prevention.
During the last 4 years I have worked with the Cardiovascular Reference group in Wandsworth working with various patient representatives as we have developed the local strategies towards prevention and the vascular health checks.
In my role as the lead for the European Atherosclerosis Society Familial Hypercholesterolaemia (FH) Studies Collaboration, I am working with patient representative organisations/charities like HEART UK, The FH Foundation and the International FH Foundation to help disseminate awareness of FH and lobby for changes in screening and how this condition is managed.
CURRENT RESEARCH GRANTS
Amgen Investigator Initiated Grant (PI)
A cross-sectional study of the management of high risk patients in Europe
European Atherosclerosis Society (EAS)
with Sanofi, Amgen, and MSD Investigator Initiated Grants (PI)
To establish the EAS endorsed Familial Hypercholesterolaemia (FH) Studies Collaboration
Pfizer Independent Grants for Learning and Change (PI)
To establish a risk prediction tool for additional lipid lowering therapies
Pfizer Global Grants for Dyslipidemia (PI)
To establish a global collaborative registry of Familial Hypercholesterolaemia (FH)
Sanofi Research Grant (PI)
Statin Intolerance analyses from CPRD
Sanofi Research Grant (PI)
To collect NHS Vascular Health Checks in South London to establish a contemporary cohort of 200 000 participants. The TOGETHER study.
CURRENT CLINICAL TRIALS
SONAR (Events Adjudication Committee Member, Sponsored by Abbvie)
An RCT of a novel endothelin inhibitor atrasentan on CV death or end stage renal disease.
Declare TIMI 58 (National Lead Investigator, Sponsored by AstraZeneca)
Multi-centre study to test if dapagliflozin when added to a patients current anti-diabetes therapy is effective in reducing cardiovascular events such as myocardial infarction (MI) (heart attack), ischemic stroke, and cardiovascular (CV) related death, compared with placebo. Enrolment of 18,000 subjects anticipated with completion expected in 2019.
STRENGTH (National Lead Investigator and Executive Committee Member, Sponsored by AstraZeneca)
Phase 3 RCT of Omega 3 Fatty acids for the secondary Prevention of CVD.
THEMIS: Phase 3 RCT (National Lead Investigator and Steering Committee Member, Sponsored by AstraZeneca)
Assessing the effect of Ticagrelor in stable CHD. Global study of 17,000 patients. Expected completion 2017.
CARAT (Executive Committee Member, Sponsored by Cerenis)
Phase 3 RCT assessing the efficacy of a HDL mimetic on atheroma burden on IVUS.
CAMELLIA TIMI 61 (Steering Committee Member, Sponsored by Eisai)
Phase 3 trial of a novel agent for weight loss improvement of metabolic traits and CVD outcomes.
CLEAR CVOT (Executive Committee Member, Sponsored by Esperion)
Phase 3 RCT assessing the efficacy of ETC1002 on CVD outcomes in patients at CVD risk intolerant of statins.
HARMONY Esperion Lipid lowering trials (Executive Committee Member, Sponsored by Esperion)
Phase 3 RCT assessing the efficacy of ETC1002 on LDL-C.
PROMINENT (Steering Committee Member, Sponsored by Kowa)
Phase 3 RCT assessing the efficacy of K877on CVD in people with DM and high TG low HDL-C. Commencing 2017.
ACCENTUATE (Executive Committee Member, Sponsored by Lilly)
Phase 3 trial of Anacetrapib on Lipid levels among those with FH or dyslipidemia intolerant of current therapies.
Lilly Phase 3 Lipid Lowering programme of a novel PCSK9 Mab. Chair of Statin Intolerance Study (Executive Committee Member, Sponsored by Lilly)
Phase 3 RCT assessing the efficacy of Mab to PCSK9 on LDL-C. Commencing 2017.
ORION 1 (PI and Co-Chair of the Executive Committee, Sponsored by Medicines Company)
Phase 2 RCT assessing the efficacy of a novel intervention with iRNA therapy to PCSK9 on lipids.
BETONMACE (Chair of International Executive Committee, Sponsored by Resverlogix)
Phase 3 RCT assessing the efficacy of BET inhibition on CVD.
Odyssey Outcomes (National Lead Investigator, Sponsored by Sanofi Regeneron)
Multi-centre study to compare the effect of alirocumab SAR236553 (REGN727) with placebo on the occurrence of cardiovascular events in patients who have experienced an acute coronary syndrome (ACS).
Odyssey Diabetes 1 (Executive Committee Member, Sponsored by Sanofi Regeneron)
Phase 3 RCT assessing the efficacy of Alirocumab on lipids in patients with atherogenic dyslipidaemia and DM.
Odyssey Diabetes 2 (Executive Committee Member, Sponsored by Sanofi Regeneron)
Phase 3 RCT assessing the efficacy of Alirocumab on lipids in patients with DM treated with insulin.
Amsterdam Medical Centre (AMC), https://www.amc.nl/web/Zorg.htm
Imperial Clinical Trials Unit (ICTU), https://www.imperial.ac.uk/clinical-trials-unit/
European Atherosclerosis Society (EAS), https://www.eas-society.org/
Harvard Clinical Research Institute (HCRI), http://www.hcri.harvard.edu/
University of Manchester, http://www.manchester.ac.uk/
University of Leicester, https://le.ac.uk/
Research Student Supervision
Bahia,S, PhD co-supervisor (St George's Univ of London), Aneurysm-CaRe: A pilot randomised controlled trial of multimodal cardiac rehabilitation versus standard care to improve cardiovascular mortality and morbidity in survivors of aortic aneurysm repair.
Brownrigg,J, PhD (St George's Univ of London), "Impact of Diabetic foot ulcers and neuropathy on CVD and all cause mortality"
Calvert,P, PhD (Univ of Cambridge), “Assessing vulnerable plaques via VH IVUS, biomarkers and DNA markers of senescense”
Ghani,S, MD co-supervisor (St George's Univ of London), Impact of Pre-participation Cardiovascular Screening using 12-lead ECG in athletes and young apparently healthy individuals in the UK
Mathew,A, MPhil in Epidemiology (Univ of Cambridge), Relationship between smoking and cardiovascular events in the Emerging Risk factors collaboration.”
Paracha,A, MSc in Preventive Cardiology (Imperial College), “Variations in lipid profiles at referral to the lipid clinic in a diverse population at St George’s Hospital, London”
Seshasai,SR, PhD (Univ of Cambridge), “Diabetes and vascular and non-vascular events in the 1 million person Emerging Risk factors collaboration.”
Willett,P, MPhil in Epidemiology (Univ of Cambridge)