Randomised trials in cardiovascular and metabolic disease

Lead Research Organisation: University of Oxford

Abstract

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 and kidney disease. 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 the decision about who receives a treatment is determined by chance (like tossing a coin). In order to help provide reliable results, 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. 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. Ongoing studies include testing a cholesterol-lowering drug added to statin therapy in people at high risk of heart problems, a new treatment for kidney disease and testing an established medication to investigate whether it can slow the worsening of eye disease in people with diabetes.

Technical Summary

This programme aims to generate reliable evidence about interventions with potential for significant public health benefit. Treatments with even modest effects in common diseases (such as vascular disease, diabetes or chronic kidney disease) may make significant contributions to reducing morbidity and mortality globally. Building on epidemiological evidence and other data generated in PHRU, CTSU and elsewhere, we aim to deliver large-scale randomised evidence to determine the efficacy and safety of treatments in cardiovascular and metabolic disease. 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 our large randomised trials (HPS, SEARCH and SHARP) and meta-analyses, statins, which effectively lower LDL cholesterol, are now very widely used for both primary and secondary prevention of cardiovascular disease. However 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 treatments on top of statins are likely to be modest, so large-scale randomised evidence is required to assess their effects reliably, hence the ORION-4 trial of a silencing RNA to PCSK9 (inclisiran) will recruit 15,000 people at high risk of cardiovascular disease. Participants will receive 6-monthly injections of inclisiran or placebo and be followed for at least 5 years at large streamlined clinics based in the UK and USA. Recent trials of sodium glucose co-transporter 2 inhibitors (SGLT2i) have shown they reduce the risk of cardiovascular disease (in particular heart failure) and progression of kidney disease among patients with diabetes. The mechanism by which SGLT2i affect kidney function does not require the presence of diabetes, so an important question in nephrology is whether SGLT2i also reduce the risk of cardiovascular disease and progression of kidney disease among patients with established chronic kidney disease, regardless of whether they have diabetes or not. The EMPA-KIDNEY trial will recruit at least 5000 participants with chronic kidney disease (at least a third with and a third without diabetes) and compare the effect of empagliflozin 10 mg daily versus placebo on a cardiorenal primary outcome. The LENS trial is also comparing an established treatment (fenofibrate) among participants with diabetic eye disease to test the hypothesis (raised by other trials) that fenofibrate may delay the progression of retinopathy.
Over the last several years, PHRU has developed streamlined methods to recruit large numbers of patients and conduct trials efficiently as well as cost-effectively (e.g. ASCEND), including 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). Such efforts will continue in the next quinquennium (including using the ongoing trials as laboratories for such methodological development) so that the outputs from this programme will not only be reliable answers to important questions in the treatment of cardiovascular and metabolic disease, but also rapidly transferable information on how to conduct such trials for use by the wider trials community.

Publications

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