Randomized trials in cardiovascular and metabolic diseases

The aim of this programme is to demonstrate reliably any benefits of treatments that can be widely used in common diseases such as heart disease, diabetes, stroke and cancer. Even quite modest improvements in outcome in common conditions can lead to important benefits for patients. In order to be sure that treatments really work, large numbers of people usually need to be given the treatment and compared with similar people not given the treatment. The most reliable way to do this is using randomisation, a method whereby who gets given a treatment is determined by chance (like tossing a coin). These randomised trials also often involve masking (or blinding) the treatment so that neither the participants nor their doctors or nurses know if they are taking an active or dummy treatment, this helps with making the study reliable. Over the past several years, we have pioneered ways of running randomised trials involving thousands of people efficiently and cost-effectively to gain reliable information. We have developed a wide experience of using IT and centrally held health records to streamline the running of large trials. Partly why statin treatments are so widely used is as a result of studies that we have run. Ongoing studies include testing aspirin in people with diabetes and a new lipid changing drug added to statin therapy in people at high risk of heart problems.

The aim of this programme is to generate reliable evidence about interventions with the potential for significant public health benefit. Treatments with even modest effects in common diseases (such as cancer, cardiovascular disease, diabetes, chronic kidney disease or osteoporosis) may make significant contributions to reducing morbidity and mortality globally. Building on epidemiological evidence generated in PHRU and elsewhere for associations between various biomarkers or risk factors (e.g. lipid markers, 25(OH) vitamin D), we aim to deliver large-scale randomised evidence to determine whether such associations are causal and reversible. Along with smoking and blood pressure, blood lipids are a major cause of cardiovascular disease, a major cause of morbidity and mortality worldwide. Higher levels of LDL cholesterol and lower levels of HDL cholesterol are associated with higher risks of coronary heart disease. Partly as a result of a series of large randomised trials (HPS, SEARCH and SHARP run by PHRU) and meta-analyses (also conducted by PHRU), statins, which effectively lower LDL cholesterol, are now very widely used for the primary and secondary prevention of cardiovascular disease. However, although widely used, available and highly cost-effective some patients remain at high risk despite statin use, thus additional safe treatments to modify risk are needed. Attention is now turning to newer drugs which modulate lipids by other mechanisms. The effects of such additional treatments on top of statins are likely to be modest, so large-scale randomised evidence are required to assess their effects reliably, hence the REVEAL trial of a cholesterol ester transfer protein inhibitor (CETPI) anacetrapib has randomized 30,000 people worldwide at risk of cardiovascular disease.
Over the last several years, PHRU has developed streamlined methods to recruit large numbers of patients and conduct trials efficiently (e.g. REVEAL) as well as cost-effectively (e.g. ASCEND), including using factorial designs to address more than one question at a time and using record linkage to facilitate follow-up, both during the trials (e.g. ASCEND, 3C, LENS) and in the longer-term (e.g. HPS, SEARCH). In addition, PHRU has piloted trials of non-commercial questions (e.g. high-dose vitamin D in older people) and of a combination of angiotensin receptor blocker and neprolysin inhibitor (ARNI) in chronic kidney disease with a view to securing funding for larger trials aiming to generate reliable evidence.
Dementia and other neurodegenerative diseases are also major causes of public health problems, and incur huge costs for families and health and social services, but they have been relatively poorly researched. Collaborating with other researchers, MADE and Schizophrenia ATLAS in neurodegenerative diseases will help answer important clinical questions and help build collaborations for the future.