Principal Investigator: Associate Professor Jemma Hopewell
Department: Nuffield Department of Population Health
Institution: University of OxfordTags: 14568, cardiovascular, genetics, risk factors, treatments
1a: Cardiovascular clinical trials are increasingly costly and, in the current era of highly effective risk modifying therapies, the plausible benefits of new compounds are modest and the need for more efficient trial designs is rising. We will conduct observational and genetic studies to elucidate the effects of established and novel cardiovascular drug targets to inform trial design and therapeutic indications. Examining observational associations can identify patient groups most likely to benefit or at risk of side-effects and examining genetic variants that mimic the biological drug target can help anticipate treatment effects, facilitating better trial designs and use of treatment.
1b: Numerous medications have been proven to be highly effective at reducing cardiovascular events in randomised trials and are now considered standard therapy for high-risk patients (e.g. statins, aspirin, blood-pressure lowering medications). However, despite improvements in our understanding and ability to manage cardiovascular risk factors, cardiovascular disease remains a leading cause of morbidity and mortality worldwide and additional therapies are needed. The proposed research will enhance our understanding of cardiovascular drug targets, improve appropriate therapeutic usage of cardiovascular drugs, facilitate improved efficiency and design of clinical trials, and promote the emergence of effective novel therapies for cardiovascular disease.
1c: The research plan will investigate:
– The associations of observational and biochemical measures on side-effects of cardiovascular therapies in relation to the expected benefit, such as bleeding and aspirin use.
– Influence of genetic variants on therapeutic targets, such as a Lp(a), and with risk factors and side-effects of cardiovascular therapies.
– Associations between genetic variants that mimic drug targets and characteristics, biomarkers, and disease in order to identify subgroup, pleiotropic and side-effects of treatment.
– Differences in the effects of drug targets by genetic and non-genetic factors.
– The methodological impact on clinical trial design and treatment use.
1d: Full cohort
Project extension February 2019:
Cardiovascular clinical trials are increasingly costly and, in the current era of highly effective risk modifying therapies, the plausible benefits of new compounds are modest. Therefore, there is a need to ensure that development of new therapies is focused on targets that are most likely to succeed and that will address the most relevant risk factors for disease, that we try and anticipate the potentially beneficial and adverse effects of therapies where possible, and that we understand how patient characteristics may influence therapeutic effects. Such insights will help to ensure streamlining of drug development, efficient design of clinical trials, and effective use of treatments, and thereby has the potential to have considerable benefits for patient care. This research focuses on the use of genetic epidemiological techniques (such as Mendelian randomization and genome-wide association studies) as well as conventional epidemiological methods (such as linear and logistic regression models) in order to robustly address the underlying hypotheses.
In summary, we will undertake genetic and observational studies to identify and to elucidate novel and established risk factors for cardiovascular/cardiac diseases (such as coronary disease, stroke, peripheral vascular disease, atrial fibrillation, heart failure), and will assess whether such risk factors are likely to be causally associated with disease. This research will enable us to establish and better understand the relevance of genetic and non-genetic risk factors for disease, and potentially mediating disease mechanisms, in order to inform and target ongoing and future drug development most efficiently.
We will undertake studies to determine and anticipate the effects of a range of therapies and to thereby also provide insights into the impact of the underlying biological mechanisms. The development and the use of genetic instruments that can be used to mimic drug mechanisms will enable us to anticipate a wide range of possible treatment effects and interactions. We will also explore effects in individuals with different characteristics in order to identify those most likely to benefit and/or at varying risks of side-effects. This information will provide insights that can be used to enhance clinical trial design, inform drug repurposing, and facilitate better use of treatments in patients.
Last updated Mar 12, 2019